Alternative titles; symbols
HGNC Approved Gene Symbol: GH1
SNOMEDCT: 237687003, 71003000;
Cytogenetic location: 17q23.3 Genomic coordinates (GRCh38): 17:63,917,203-63,918,839 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q23.3 | Growth hormone deficiency, isolated, type IA | 262400 | Autosomal recessive | 3 |
| Growth hormone deficiency, isolated, type IB | 612781 | 3 | ||
| Growth hormone deficiency, isolated, type II | 173100 | Autosomal dominant | 3 | |
| Kowarski syndrome | 262650 | Autosomal recessive | 3 |
Growth hormone (GH) is synthesized by acidophilic or somatotropic cells of the anterior pituitary gland. Human growth hormone has a molecular mass of 22,005 and contains 191 amino acid residues with 2 disulfide bridges (Niall et al., 1971).
By 1977, not only had the amino acid sequence of GH been determined, but the sequence of nucleotides in the structural gene for GH had been determined as well (Baxter et al., 1977).
By molecular cloning of cDNA, Masuda et al. (1988) demonstrated that the 20-kD variant of human GH is produced by the same gene (GHN or GH1) as the 22-kD form, and that a process of alternative splicing is involved.
Chen et al. (1989) sequenced the entire 66,500 bp of the GH gene cluster. The expression of the 5 genes in this cluster was examined by screening pituitary and placenta cDNA libraries, using gene-specific oligonucleotides. According to this analysis, the GHN gene is transcribed exclusively in the pituitary, whereas the other 4 genes (CSL, 603515; CSA, 150200; GHV, 139240; and CSB, 118820) are expressed only in placental tissues. The CSL gene carries a G-to-A transition in a sequence used by the other 4 genes as an intronic 5-prime splice donor site. The mutation results in a different splicing pattern and, hence, in a novel sequence of the CSL gene mRNA and the deduced polypeptide.
GH and CSH (CSA) have 191 amino acid residues and show about 85% homology in amino acid sequence (Owerbach et al., 1980). Their messenger RNAs have more than 90% homology.
Human GH binds 2 GHR (600946) molecules and induces signal transduction through receptor dimerization. Sundstrom et al. (1996) noted that at high concentrations, GH acts as an antagonist because of a large difference in affinities at the respective binding sites. This antagonist action can be enhanced further by reducing binding in the low-affinity binding site. A possible mechanism by which mutant, biologically inactive GH may have its effect is to act as an antagonist to the binding of normal GH to its receptor, GHR.
The regulation of GH synthesis and release is modulated by a family of genes that include the transcription factors PROP1 (601538) and PIT1 (173110). PROP1 and PIT1 regulate differentiation of pituitary cells into somatotrophs, which synthesize and release GH. Genes that are important in the release of GH include the GHRH (139190) and GHRHR (139191) genes. After GHRH is synthesized and released from the hypothalamus, it travels to the anterior pituitary where it binds to GHRHR, resulting in transduction of a signal into the somatotroph which promotes release of presynthesized GH that is stored in secretory granules. Other gene products that are important in GH synthesis and release are GHR and the growth hormone-binding proteins (GHBP). The GHBPs are derived from the membrane bound receptor (GHR) and they remain bound to GH in the circulation. Following binding of GH to 2 GHR molecules, the signal to produce IGF1 (147440) is transduced. The GH molecules that are bound to membrane-anchored GH receptors can be released into the circulation by excision of the extracellular portion of the GHR molecules. At this point, the extracellular portion of the GHR, which is referred to as the GHBP, serves to stabilize GH in the circulation. The final genes in the GH synthetic pathway include IGF1 and its receptor (IGF1R; 147370), whose products stimulate growth in various tissues including bones and muscle (Phillips, 1995; Rimoin and Phillips, 1997).
Boguszewski et al. (1997) investigated the proportion of circulating non-22-kD GH1 isoforms in prepubertal children with short stature (height less than -2 SD score) of different etiologies. The study groups consisted of 17 girls with Turner syndrome (TS), aged 3 to 13 years; 25 children born small for gestational age (SGA) without postnatal catch-up growth, aged 3 to 13 years; and 24 children with idiopathic short stature (ISS), aged 4 to 15 years. The results were compared with those from 23 prepubertal healthy children of normal stature (height +/- 2 SD score), aged 4 to 13 years. Serum non-22-kD GH levels, expressed as a percentage of the total GH concentration, were determined by the 22-kD GH exclusion assay. The median proportion of non-22-kD GH isoforms was 8.1% in normal children; it was increased in children born SGA (9.8%; P = 0.05) and in girls with TS (9.9%; P = 0.01), but not in children with ISS (8.9%). In children born SGA, the proportion of non-22-kD GH isoforms directly correlated with different estimates of spontaneous GH secretion and inversely correlated with height SD score. The authors concluded that the ratio of non-22-kD GH isoforms in the circulation may have important implications for normal and abnormal growth.
Mendlewicz et al. (1999) studied the contributions of genetic and environmental factors in the regulation of the 24-hour GH secretion. The 24-hour profile of plasma GH was obtained at 15-minute intervals in 10 pairs of monozygotic and 9 pairs of dizygotic normal male twins, aged 16 to 34 years. A major genetic effect was evidenced on GH secretion during wakefulness (heritability estimate of 0.74) and, to a lesser extent, on the 24-hour GH secretion. Significant genetic influences were also identified for slow-wave sleep and height. These results suggested that human GH secretion in young adulthood is markedly dependent on genetic factors.
Hindmarsh et al. (1999) studied GH secretory patterns in the elderly by constructing 24-hour serum GH profiles in 45 male and 38 female volunteers, aged 59.4 to 73.0 years, and related patterns to IGF1, IGFBP3 (146732), and GH-binding protein levels; body mass index; and waist/hip ratio. There was a highly significant difference in mean 24-hour serum GH concentrations in females compared to males as a result of significantly higher trough GH levels in females. Peak values were not significantly different. Serum IGF1 levels were significantly higher in males. Peak GH values were related to serum IGF1 levels, whereas trough GH levels were not. GH was secreted with a dominant periodicity of 200 minutes in males and 280 minutes in females. GH secretion assessed by ApEn was more disordered in females, and increasing disorder was associated with lower IGF1 levels. Body mass index was negatively related to GH in both sexes. In males, trough values were the major determinant, whereas in females, the peak value was the major determinant. Trough GH levels were inversely related in both sexes to waist/hip ratio and to increasing secretory disorder. These data demonstrated a sexually dimorphic pattern of GH secretion in the elderly.
De Groof et al. (2002) evaluated the GH/IGF1 axis and the levels of IGF-binding proteins (IGFBPs), IGFBP3 protease, glucose, insulin (176730), and cytokines in 27 children with severe septic shock due to meningococcal sepsis during the first 3 days after admission. The median age was 22 months. Significant differences were found between nonsurvivors and survivors for the levels of total IGF1, free IGF1, IGFBP1 (146730), IGFBP3 protease activity, IL6 (147620), and TNFA (191160). The pediatric risk of mortality score correlated significantly with levels of IGFBP1, IGFBP3 protease activity, IL6, and TNFA and with levels of total IGFI and free IGFI. Levels of GH and IGFBP1 were extremely elevated in nonsurvivors, whereas total and free IGFI levels were markedly decreased and were accompanied by high levels of the cytokines IL6 and TNFA.
In rodents and humans there is a sexually dimorphic pattern of GH secretion that influences the serum concentration of IGF1. Geary et al. (2003) studied the plasma concentrations of IGF1, IGF2 (147470), IGFBP3, and GH in cord blood taken from the offspring of 987 singleton Caucasian pregnancies born at term and related these values to birth weight, length, and head circumference. Cord plasma concentrations of IGF1, IGF2, and IGFBP3 were influenced by factors related to birth size: gestational age at delivery, mode of delivery, maternal height, and parity of the mother. Plasma GH concentrations were inversely related to the plasma concentrations of IGF1 and IGFBP3; 10.2% of the variability in cord plasma IGF1 concentration and 2.7% for IGFBP3 was explained by sex of the offspring and parity. Birth weight, length, and head circumference measurements were greater in males than females (P less than 0.001). Mean cord plasma concentrations of IGF1 and IGFBP3 were significantly lower in males than females. Cord plasma GH concentrations were higher in males than females, but no difference was noted between the sexes for IGF2. After adjustment for gestational age, parity, and maternal height, cord plasma concentrations of IGF1 and IGFBP3 along with sex explained 38.0% of the variability in birth weight, 25.0% in birth length, and 22.7% in head circumference.
Ho et al. (2002) noted that the human GH gene cluster encompasses GHN, which is expressed primarily in pituitary somatotropes, and 4 genes, CSA, CSB, CSL, and GHV, which are expressed specifically in syncytiotrophoblast cells lining the placental villi. A multicomponent locus control region (LCR) is required for transcriptional activation in both pituitary and placenta. In addition, 2 genes overlap with the GH LCR: SCN4A (603967) on the 5-prime end and CD79B (147245) on the 3-prime end. Ho et al. (2002) studied mice carrying an 87-kb human transgene encompassing the GH LCR and most of the GH gene cluster. By deleting a fragment of the transgene, they showed that a single determinant of the human GH LCR located 14.5 kb 5-prime to the GHN promoter has a critical, specific, and nonredundant role in facilitating promoter trans factor binding and activating GHN transcription. Ho et al. (2002) found that this same determinant plays an essential role in establishing a 32-kb acetylated domain that encompasses the entire GH LCR and the contiguous GHN promoter. These data supported a model for long-range gene activation via LCR-mediated targeting and extensive spreading of core histone acetylation.
Using mice carrying the 87-kb human GH transgene, Ho et al. (2006) found that insertion of a Pol II terminator within the GH LCR blocked transcription of the CD79B gene adjacent to the LCR and repressed GHN expression. However, the insertion had little effect on acetylation within the GH locus. Selective elimination of CD79B also repressed GHN expression. Ho et al. (2006) concluded that Pol II tracking and histone acetylation are not linked and that transcription, but not translation, of the CD79B gene is required for GHN expression.
The human CD79B/GH locus contains 6 tightly linked genes with 3 mutually exclusive tissue specificities and interdigitated control elements. Consequently, pituitary cell-specific transcriptional events that activate GHN ectopically activate CD79B, whereas B lymphocyte-specific events that activate CD79B do not activate GHN. Using DNase I hypersensitive site mapping, chromatin immunoprecipitation assays of human and mouse cell lines, and transgenic mouse models, Yoo et al. (2006) found tissue-specific patterns of chromatin structure and transcriptional controls at the CD79B/GH locus in B cells that were distinct from those in pituitary gland and placenta. Yoo et al. (2006) proposed that such gene expression pathways and transcriptional interactions are likely to be juxtaposed at multiple sites within eukaryote genomes.
In addition to expression in pituitary and placenta and functions in growth and reproduction, prolactin (PRL; 176760), GH, and placental lactogen (CSH1; 150200) are expressed in endothelial cells and have angiogenic effects. Ge et al. (2007) found that BMP1 (112264) and BMP1-like proteinases processed PRL and GH in vitro and in vivo to produce approximately 17-kD N-terminal fragments with antiangiogenic activity.
The GH, PL (CSH1), and PRL genes contain 5 exons. The 4 introns occur at the same sites, supporting evolutionary homology (Baxter, 1981). All 5 genes in the GH gene cluster are in the same transcriptional orientation (Ho et al., 2002).
Baxter (1981) found evidence for the existence of at least 3 GH and 3 CSH, also called placental lactogen (PL), genes on chromosome 17. Whether they are situated GH:GH:GH:PL:PL:PL or arranged GH:PL:GH:PL:GH:PL was not clear.
Crystal Structure
Sundstrom et al. (1996) crystallized a GH antagonist mutant, gly120 to arg, with its receptor as a 1-to-1 complex and determined the crystal structure at 2.9-angstrom resolution. The 1-to-1 complex with the agonist is remarkably similar to the native GHR 1-to-2 complex. A comparison between the 2 structures revealed only minimal differences in the conformations of the hormone or its receptor in the 2 complexes.
Owerbach et al. (1980) estimated that the GH and CSH genes diverged about 50 to 60 million years ago, whereas the PRL and GH genes diverged about 400 million years ago.
Human PL and human GH are more alike than are rat GH and human GH. (PL has more growth-promoting effects than milk-producing effects.) Baxter (1981) proposed that in evolution the prolactin gene diverged early from the gene that was the common progenitor of the GH and PL genes. (Placental lactogen was the official Endocrine Society designation; Grumbach (1981) promoted the term chorionic somatomammotropin, which has functional legitimacy.)
By a combination of restriction mapping and somatic cell hybridization, Owerbach et al. (1980) assigned genes for growth hormone, chorionic somatomammotropin (CSH), and a third growth hormone-like gene (GH2; 139240) to the growth hormone gene cluster that is assigned to chromosome 17.
Lebo (1980) corroborated the assignment of the GH gene to chromosome 17 by the technique of fluorescence-activated chromosome sorting. George et al. (1981) assigned the genes for GH and CSH to the 17q21-qter region.
Ruddle (1982) found that the GH family of genes is between galactokinase (604313) and thymidine kinase (TK1; 188300), with galactokinase being closer to the centromere.
Harper et al. (1982) used in situ hybridization to assign the GH gene cluster to 17q22-q24. A gene copy number experiment showed that both genes are present in about 3 copies per haploid genome. The sequence of genes in the GH gene cluster is thought to be GHN--CSL--CSA--GHV--CSB (Phillips, 1983). Normal growth hormone (GHN, referred to now as GH1) encodes GH. CSA and CSB both encode chorionic somatomammotropin. GHV, or growth hormone variant, is now designated GH2.
Xu et al. (1988) assigned the growth hormone complex to 17q23-q24 by in situ hybridization.
Using GH cDNA as a specific DNA probe in Southern blot analyses, Phillips et al. (1981) found that the GHN (GH1) gene was deleted in 2 families with type IA growth hormone deficiency (Illig type; 262400). On the other hand, the GH genes of persons with type IB (612781) (in 6 families) had normal restriction patterns. Two affected sibs in 2 of the 6 families were discordant for 2 restriction markers closely linked to the GH cluster.
Braga et al. (1986) reported the cases of a son and daughter of first-cousin Italian parents who had isolated growth hormone deficiency (IGHD) resulting from homozygosity for a 7.6-kb deletion within the GH gene cluster. Both developed antibodies in response to treatment with human GH, but in neither was there interference with growth. The deletion affected not only the structural gene for GH (GH1) but also sequences adjacent to CSL.
Goossens et al. (1986) described a double deletion in the GH gene cluster in cases of inherited growth hormone deficiency. A total of about 40 kb of DNA was absent due to 2 separate deletions flanking the CSL gene (603515). Two affected sibs were homozygous. The parents were described as 'Romany of French origin' and were related as first cousins once removed. Restriction patterns in them were consistent with heterozygosity.
Vnencak-Jones et al. (1988) described the molecular basis of deletions within the human GH gene cluster in 9 unrelated patients. Their results suggested that the presence of highly repetitive DNA sequences flanking the GH1 gene predisposed to unequal recombinant events through chromosomal misalignment.
In a Chinese family, He et al. (1990) found that 2 sibs with GH deficiency had a deletion of approximately 7.1 kb of DNA. The parents, who were related as second cousins, were heterozygous but of normal stature. The affected children had not received exogenous GH, but the authors suspected that their disorder represented IGHD type IA.
Akinci et al. (1992) described a Turkish family in which 3 children had IGHD type IA. A homozygous deletion of approximately 45 kb encompassing the GH1, CSL, CSA, and GH2 genes was found. The end points of the deletion lay within 2 regions of highly homologous DNA sequence situated 5-prime to the GH1 gene and 5-prime to the CSB gene. The parents, who were consanguineous, were both heterozygous for the deletion.
Mullis et al. (1992) analyzed GH1 DNA from circulating lymphocytes of 78 subjects with severe IGHD. The subjects analyzed were broadly grouped into 3 different populations: 32 north European, 22 Mediterranean, and 24 Turkish. Of the 78 patients, 10 showed a GH1 deletion; 8 had a 6.7-kb deletion, and the remaining 2 had a 7.6-kb GH1 deletion. Five of the 10 subjects developed anti-hGH antibodies to hGH replacement followed by a stunted growth response. Parental consanguinity was found in all families, and heterozygosity for the corresponding deletion was present in each parent. The proportion of deletion cases was about the same in each of the 3 population groups.
Phillips and Cogan (1994) tabulated mutations found in the GH gene.
Takahashi et al. (1996) reported the case of a boy with short stature and heterozygosity for a mutant GH gene (139250.0008). In this child, the GH not only could not activate the GH receptor (GHR; 600946) but also inhibited the action of wildtype GH because of its greater affinity for GHR and GH-binding protein (GHBP), which is derived from the extracellular domain of the GHR. Thus, a dominant-negative effect was observed. See Kowarski syndrome, 262650.
Splicing of pre-mRNA transcripts is regulated by consensus sequences at intron boundaries and the branch site. In vitro studies showed that the small introns of some genes also require intron splice enhancers (ISE) to modulate splice site selection. An autosomal dominant form of isolated growth hormone deficiency (IGHD II; 173100) can be caused by mutations in intron 3 (IVS3) of the GH1 gene that cause exon 3 skipping, resulting in truncated GH1 gene products that prevent secretion of normal GH. Some of these GH1 mutations are located 28 to 45 nucleotides into IVS3 (which is 92 nucleotides long). McCarthy and Phillips (1998) localized this ISE by quantitating the effects of deletions within IVS3 on skipping of exon 3. The importance of individual nucleotides to ISE function was determined by analyzing the effects of point mutants and additional deletions. The results showed that (1) an ISE with a G(2)X(1-4)G(3) motif resides in IVS3 of the GH1 gene; (2) both runs of Gs are required for ISE function; (3) a single copy of the ISE regulates exon 3 skipping; and (4) ISE function can be modified by an adjacent AC element. The findings revealed a new mechanism by which mutations can cause inherited human endocrine disorders and suggested that (1) ISEs may regulate splicing of transcripts of other genes, and (2) mutations of these ISEs or of the transacting factors that bind them may cause other genetic disorders.
Hasegawa et al. (2000) studied polymorphisms in the GH1 gene that were associated with altered GH production. The subjects included 43 prepubertal short children with GHD without gross pituitary abnormalities, 46 short children with normal GH secretion, and 294 normal adults. A polymorphism in intron 4 (A or T at nucleotide 1663, designated P1) was identified. Two additional polymorphic sites (T or G at nucleotide 218, designated P2, and G or T at nucleotide 439, designated P3) in the promoter region of the GH1 gene were also identified and matched with the P1 polymorphism (A or T, respectively) in more than 90% of the subjects. P1, P2, and P3 were considered to be associated with GH production. For example, the allele frequency of T at P2 in prepubertal short children with GHD without gross pituitary abnormalities (58%) was significantly different from that in short children with normal GH secretion and normal adults (37% and 44%, respectively). Furthermore, significant differences were observed in maximal GH peaks in provocative tests, IGF1 (147440) SD scores, and height SD scores in children with the T/T or G/G genotypes at P2. In the entire study group, significant differences in IGF1 SD scores and height SD scores were observed between the T/T and G/G genotypes at P2. Hasegawa et al. (2000) concluded that GH secretion is partially determined by polymorphisms in the GH1 gene, explaining some of the variations in GH secretion and height.
Dennison et al. (2004) examined associations between common SNPs in the GH1 gene and weight in infancy, adult bone mass and bone loss rates, and circulating GH profiles. Genomic DNA was examined for 2 SNPs in the GH gene, 1 in the promoter region and 1 in intron 4. Homozygotes at loci GH1 A5157G and T6331A displayed low baseline bone density and accelerated bone loss; there was also a significant (P = 0.04) interaction among weight at 1 year, GH1 genotype, and bone loss rate. There was a graded association between alleles and circulating GH concentration among men. The authors concluded that common diversity in the GH1 region predisposes to osteoporosis via effects on the level of GH expression.
The proximal promoter region of the GH1 gene is highly polymorphic, containing at least 15 SNPs. This variation is manifest in 40 different haplotypes, the high diversity being explicable in terms of gene conversion, recurrent mutation, and selection. Horan et al. (2003) showed by functional analysis that 12 haplotypes were associated with a significantly reduced level of reporter gene expression, whereas 10 haplotypes were associated with a significantly increased level. The former tended to be more prevalent in the general population than the latter (p less than 0.01), possibly as a consequence of selection. Haplotype partitioning identified 6 SNPs as major determinants of GH1 gene expression, which is influenced by an LCR located between 14.5 and 32 kb upstream of the GH1 gene (Jones et al., 1995). Horan et al. (2003) used a series of LCR-GH1 proximal promoter constructs to demonstrate that the LCR enhanced proximal promoter activity by up to 2.8-fold depending upon proximal promoter haplotype, and that the activity of a given proximal promoter haplotype was also differentially enhanced by different LCR haplotypes. The genetic basis of interindividual differences in GH1 gene expression thus appeared to be extremely complex.
Millar et al. (2003) sought to identify subtle mutations in the GH1 gene, which had been regarded as a comparatively rare cause of short stature, in 3 groups: 41 individuals selected for short stature, reduced height velocity, and bone age delay, 11 individuals with short stature and IGHD, and 154 controls. Heterozygous mutations were identified in all 3 groups but disproportionately in the individuals with short stature, both with and without IGHD. Twenty-four novel GH1 gene lesions were found. Fifteen novel GH1 gene mutations were considered to be of probable phenotypic significance. Although most such lesions may be insufficient on their own to account for the observed clinical phenotype, they were considered likely to play a contributory role in the etiology of short stature.
In a screen of the GH1 gene for mutations in a group of 74 children with familial short stature, Lewis et al. (2004) identified 4 mutations, 2 of which were novel: an ile179-to-met (I179M) substitution and a single-basepair substitution in the promoter region. Resistance to proteolysis and secretion from rat pituitary cells of I179M GH were consistent with a lack of significant misfolding. Receptor binding studies were normal, but molecular modeling studies suggested that the I179M substitution might perturb interactions between GH and the GH receptor loop containing residue trp169, thereby affecting signal transduction. In contrast to its ability to activate STAT5 (601511) normally, activation of ERK (see 176948) by the I179M variant was reduced to half that observed with wildtype. The subject exhibited normal GH secretion after pharmacologic stimulation. That the I179M variant did not cosegregate with the short stature phenotype in the family strongly suggested to Lewis et al. (2004) that this variant was on its own insufficient to fully account for the observed clinical phenotype.
Cogan et al. (1995, 1997) and Moseley et al. (2002) described 3 mutations (139250.0016; 139250.0011; 139250.0012) that are not located at the 5-prime splice site in intron 3 but still alter splicing of GH1 to cause increased production of a 17.5-kD isoform. All 3 mutations reside within purine-rich sequences that resemble exonic and intronic splicing enhancers (ESE and ISE). Since splicing enhancers often activate specific splice sites to facilitate exon definition, Ryther et al. (2003) considered that the splicing defects caused by these mutations could be due to a defect in exon definition, resulting in exon skipping. They showed that overexpression of the dominant-negative 17.5-kD isoform also destroyed the majority of somatotrophs, leading to anterior pituitary hypoplasia in transgenic mice. They demonstrated that dual splicing enhancers are required to ensure exon 3 definition to produce full-length 22-kD hormone. They also showed that splicing enhancer mutations that weaken exon 3 recognition produce variable amounts of the 17.5-kD isoform, a result that could potentially explain the clinical variability observed in IGHD II. Noncanonical splicing mutations that disrupt splicing enhancers, such as those represented by the 3 mutations discussed, demonstrate the importance of enhancer elements in regulating alternative splicing to prevent human disease.
Mullis et al. (2005) studied a total of 57 subjects with IGHD type II (173100) belonging to 19 families with different splice site as well as missense mutations within the GH1 gene. The subjects presenting with a splice site mutation within the first 2 bp of intervening sequence 3 (5-prime IVS +1/+2 bp; 139250.0009) leading to a skipping of exon 3 were more likely to present in the follow-up with other pituitary hormone deficiencies. In addition, although the patients with missense mutations had been reported to be less affected, a number of patients presenting with a missense GH form showed some pituitary hormone impairment. The development of multiple hormonal deficiencies is not age-dependent, and there is a clear variability in onset, severity, and progression, even within the same families. Mullis et al. (2005) concluded that the message of clinical importance from these studies is that the pituitary endocrine status of all such patients should continue to be monitored closely over the years because further hormonal deficiencies may evolve with time.
Shariat et al. (2008) studied a 4-generation family segregating autosomal dominant growth hormone deficiency and identified a heterozygous missense mutation in the GH gene (EX3+1G-A; 139250.0025) in affected individuals. Analysis of the effects of this variant as well as G-T and G-C changes at the first nucleotide of exon 3 illustrated the multiple mechanisms by which changes in sequence can cause disease: splice site mutations, splicing enhancer function, messenger RNA decay, missense mutations, and nonsense mutations. The authors noted that for IGHD II, only exon skipping leads to production of the dominant-negative isoform, with increasing skipping correlating with increasing disease severity.
Horan et al. (2006) observed an association between 4 core promoter haplotypes in the GH1 gene and increased risk for hypertension and stroke in a study of 111 hypertensive patients and 155 stroke patients. The association was more significant for females than males. Horan et al. (2006) also observed an association between an isoform of the GHR gene lacking exon 3 (GHRd3) and hypertension in female stroke patients. The authors postulated a complex interaction between variants in the GH1 and GHR genes involving height.
Giordano et al. (2008) studied the contribution to IGHD of genetic variations in the GH1 gene regulatory regions. The T allele of a G-to-T polymorphism at position -57 (rs2005172), within the vitamin D-responsive element, showed a positive significant association when comparing patients with normal (P = 0.006) or short stature (P = 0.0011) controls. The genotype -57TT showed an odds ratio of 2.93 (1.44-5.99) and 2.99 (1.42-6.31), respectively. Giordano et al. (2008) concluded that the common -57G-T polymorphism contributes to IGHD susceptibility, indicating that it may have a multifactorial etiology.
By Southern analysis of DNA from mouse-rat somatic cell hybrids, Cooke et al. (1986) found that the GH gene is on rat chromosome 10 and the PRL gene (176760) is on rat chromosome 17. Thus, in the rat, as in man, these genes are on different chromosomes even though they show an evolutionary relationship.
Morgan et al. (1987) showed that retrovirus-mediated gene transfer can be used to introduce a recombinant human GH1 gene into cultured human keratinocytes. The transduced keratinocytes secreted biologically active GH into the culture medium. When grafted as an epithelial sheet onto athymic mice, these cultured keratinocytes reconstituted a normal-appearing epidermis from which, however, human growth hormone could be extracted. Transduced epidermal cells may be a general vehicle for the delivery of gene products by means of grafting.
Smith et al. (1997) demonstrated a role of GH in retinal neovascularization, which is the major cause of untreatable blindness. They found that retinal neovascularization was inhibited in transgenic mice expressing a GH antagonist gene and in normal mice given an inhibitor of GH secretion. In these mice retinal neovascularization was inhibited in inverse proportion to serum levels of GH and IGF1. Inhibition was reversed with exogenous IGF1 administration. GH inhibition did not diminish hypoxia-stimulated retinal vascular endothelial growth factor (VEGF; 192240) or VEGF receptor (VEGFR; 191306) expression. Smith et al. (1997) suggested that systemic inhibition of GH or IGF1, or both, may have therapeutic potential in preventing some forms of retinopathy.
Growth hormones from primates are unique in that they are able to bind with and activate both primate and nonprimate GHRs, whereas GHs from nonprimates are ineffective in primates. Behncken et al. (1997) investigated the basis of primate specificity of binding by the GHR. They examined the interaction between GHR residues arg43 (primate) or leu43 (nonprimate) and their complementary hormone residues asp171 (primate) and his170 (nonprimate). They found that the interaction between arg43 and his170/171 is sufficient to explain virtually all of the primate species specificity.
In mouse preadipocytes, Wolfrum et al. (2003) found that Foxa2 (600288) inhibited adipocyte differentiation by activating transcription of preadipocyte factor-1 (DLK1; 176290), and that expression of both Foxa2 and Dlk1 was enhanced by growth hormone in primary preadipocytes. Wolfrum et al. (2003) suggested that the antiadipogenic activity of growth hormone is mediated by Foxa2.
Using GH-deficient Socs2 (605117) -/- mice, Greenhalgh et al. (2005) demonstrated that the Socs2 -/- phenotype is dependent upon the presence of endogenous GH. Treatment with exogenous GH induced excessive growth in terms of overall body weight, body and bone lengths, and the weight of internal organs and tissues. Microarray analysis on liver RNA extracts after exogenous GH administration revealed a heightened response to GH. The conserved C-terminal SOCS-box motif was essential for all inhibitory function. SOCS2 was found to bind 2 phosphorylated tyrosines on the GH receptor, and mutation analysis of these amino acids showed that both were essential for SOCS2 function. Greenhalgh et al. (2005) concluded that SOCS2 is a negative regulator of GH signaling.
Igarashi et al. (1993) identified a Japanese patient with growth retardation (IGHD IA; 262400) with a compound heterozygous pattern consisting of total deletion of 1 GH1 gene and retention of a GH1 gene of apparently normal size. DNA sequence analysis demonstrated deletion of 2 bases of exon 3 of 1 GH1 allele of the mother and the patient. The father carried a 6.7-kb deletion (139250.0003), present also on the patient's paternal allele. The patient was a 13-year-old female, the offspring of healthy, nonconsanguineous parents. GH therapy, begun at the age of 9 years and 2 months, resulted in catch-up growth without development of anti-GH antibodies. Deletion of the 2 bases in exon 3 was predicted to introduce a termination codon after the codon of amino acid residue 131 in exon 4.
In a Turkish family with isolated growth hormone deficiency type IA (IGHD1A; 262400), Cogan et al. (1993) found a G-to-A transition converting codon 20 from tryptophan (TGG) to stop (TAG) in the signal peptide of GH1. The mutation resulted in termination of translation after residue 19 of the signal peptide and no production of mature GH. Patients homozygous for the mutation had no detectable GH and produced anti-GH antibodies in response to exogenous GH treatment.
Duquesnoy et al. (1990) described the cases of 2 sibs with isolated growth hormone deficiency type IA (IGHD1A; 262400) who were found to be compound heterozygous for deletion and frameshift mutations in the GH1 gene. Southern blot analysis showed them to be heterozygous for a 6.7-kb GH deletion; DNA sequence analysis demonstrated deletion of a cytosine at position 371, resulting in a frameshift within the signal peptide coding region which prevented the synthesis of any mature GH protein (139250.0004). The patients presented with severe growth failure, and after an initial growth response to treatment with exogenous GH, developed high titers of anti-GH antibodies.
Vnencak-Jones et al. (1990) and Igarashi et al. (1993) also described patients with 6.7-kb deletions deleting 1 GH1 allele.
For discussion of the 1-bp deletion in the GH1 gene (371delC) that was found in compound heterozygous state in 2 sibs with isolated growth hormone deficiency type IA (IGHD1A; 262400) by Duquesnoy et al. (1990), see 139250.0003.
In a consanguineous Saudi Arabian family with isolated growth hormone deficiency type IB (IGHD1B; 612781), Cogan et al. (1993) detected a G-to-C transversion of the first base of the donor splice site of intron 4 as the basis of growth hormone deficiency. The effect of this mutation on mRNA splicing was determined by transfecting the mutant gene into cultured mammalian cells and DNA sequencing the resulting GH cDNAs. Mutation was found to cause the activation of a cryptic splice site 73 bases upstream of the exon 4 donor splice site. The altered splicing resulted in loss of amino acids 103 to 126 of exon 4 and created a frameshift that altered the amino acids encoded by exon 5.
In a consanguineous Saudi family with isolated growth hormone deficiency type IB (IGHD1B; 612781), Phillips and Cogan (1994) found a mutation at the same nucleotide as that described in 139250.0005. A G-to-T transversion in the first base of the donor splice site of intron 4 had the same effect on splicing as the G-to-C transversion. Patients homozygous for these 2 different defects in 2 different families responded well to exogenous GH treatment and did not develop anti-GH antibodies. Analogous splicing mutations occurred in the beta-globin gene, causing milder forms of beta-thalassemia called beta-plus-thalassemia.
Phillips and Cogan (1994) demonstrated a T-to-C transition in the sixth base of the donor splice site of intron 3 in a Turkish family with isolated growth hormone deficiency type II (IGHD2; 173100). The mutant GH gene was transfected into cultured mammalian cells, and the GH mRNA transcripts were analyzed by direct sequencing of their corresponding cDNAs. The mutation was found to inactivate the donor splice site of intron 3, resulting in alternative use of the donor splice site of intron 2 in conjunction with the acceptor site of intron 3. This alternative splicing pattern deleted or skipped exon 3, resulting in the loss of amino acids 32 to 71 from the corresponding mature GH protein products. All affected members of the family were heterozygous for the mutation and had low but measurable GH levels after stimulation. All responded well to treatment with exogenous GH. The mechanism of the dominant-negative effect is unknown; the mutant GH allele may inactivate the normal GH allele by formation of GH dimers or disruption of normal intracellular protein transport.
Takahashi et al. (1996) reported a patient with short stature in whom the bioactivity of growth hormone was below the normal range (Kowarski syndrome; 262650). The patient was heterozygous for a C-to-T transition in the GH1 gene that converted codon 77 from CGC (arg) to TGC (cys) (R77C). Isoelectric focusing of the proband's serum revealed the presence of an abnormal growth hormone peak in addition to the normal peak. Further studies demonstrated that the child's growth hormone not only could not activate the growth hormone receptor but also inhibited the action of wildtype growth hormone because of its greater affinity for growth hormone-binding protein and growth hormone receptor.
Petkovic et al. (2007) identified heterozygosity for the R77C mutation in a Syrian boy with short stature and partial GH insensitivity. His mother and grandfather had the same mutation and showed partial GH insensitivity with modest short stature. Functional analyses showed no differences in the binding affinity or bioactivity between wildtype and GH-R77C, nor were differences found in the extent of subcellular localization within endoplasmic reticulum, Golgi, or secretory vesicles between wildtype and GH-R77C. There was, however, a reduced capability of GH-R477C to induce GHR/GHBP gene transcription rate when compared to wildtype GH. Petkovic et al. (2007) concluded that reduced GHR/GHBP expression might be a cause of the partial GH insensitivity with delay in growth in this family.
Cogan et al. (1995) reported a G-to-A transition of the first base of the donor splice site of intron 3 (IVS3+1G-A) in the GH1 gene in subjects with isolated growth hormone deficiency type II (IGHD2; 173100) from 3 unrelated kindreds from Sweden, North America, and South Africa. This transition created an NlaIII site that was used to demonstrate that all affected individuals in all 3 families were heterozygous for the mutation. In expression studies the transition was found to destroy the GH intron 3 donor splice site, causing skipping of exon 3 and loss of amino acids 32 to 71 of the mature GH peptide from the mutant GH mRNA. Microsatellite analysis indicated that the mutation arose independently in each family. In 1 family, the finding that neither grandparent had the mutation suggests that it arose de novo.
Hayashi et al. (1999) identified 2 mutations in Japanese patients with IGHD2, G-to-A transitions at the first (mutA) and fifth (mutE; 139250.0014) nucleotides of intron 3. GH1 mRNAs skipping exon 3 were transcribed from both mutant genes. The authors studied the synthesis and secretion of GH encoded by the mutant GH1 genes and tested whether inhibition of wildtype GH secretion by mutant products could be demonstrated in cultured cell lines. A metabolic labeling study in COS-1 cells revealed that a mutant GH with a reduced molecular mass was synthesized from the mutant mRNAs and retained in the cells for at least 6 hours. On the other hand, the wildtype GH was rapidly secreted into the medium. Coexpression of mutant and wildtype GH did not result in any inhibition of wildtype GH secretion in COS-1 or HepG2 cells. However, coexpression of mutant GH resulted in significant inhibition of wildtype GH secretion in somatotroph-derived MtT/S cells as well as in adrenocorticotroph-derived AtT-20 cells, without affecting cell viability. Hayashi et al. (1999) concluded that the dominant-negative effect of mutant GH on the secretion of wildtype GH is at least in part responsible for the pathogenesis of IGHD2. They also suggested that neuroendocrine cell type-specific mechanisms, including intracellular storage of the secretory proteins, are involved in the inhibition.
Saitoh et al. (1999) described a 1-year-old Japanese boy and his father with IGHD2, both of whom had a G-to-A transition of the first base of the donor splice site of intron 3 of the GH1 gene. The mutation occurred de novo in the father. No unaffected family members had the mutation.
Binder and Ranke (1995) reported a G-to-C transversion of the first base of the donor splice site of intron 3 (IVS3+1G-C) in the GH1 gene in a sporadic case of isolated growth hormone deficiency type II (IGHD2; 173100) in a German patient. This mutation was dominant negative and arose de novo. They also reported RT-PCR data suggesting overexpression of the mutant GH1 allele and speculated that the dominant-negative effect might occur because of this imbalance in expression of the mutant and normal alleles. However, Binder et al. (1996) found equal quantities of transcripts in studies using an RNA protection assay to determine the relative expression of the intron 3 +1 G-to-C mutant and normal GH1 alleles. In normal pituitary, they found 3 GH1 mRNA species with the variant lacking exon 3, which comprised approximately 5% of the total GH1 mRNA. In contrast, lymphoblasts from the proband, who was heterozygous for the transition at intron 1, contained equal amounts of mRNA with or without exon 3. Furthermore, secreted GH1, measured by enzyme-linked immunosorbent assay, was present in equal concentrations in media from normal and mutant cells. Thus, GH1 mRNA lacking exon 3 was expressed in proportion to the dosage of the mutant gene, and dominant-negative effects on GH1 secretion were not seen in lymphoblasts. Their findings are compatible with a dominant-negative mechanism involving interaction between normal and mutant proteins in secretory vesicles of somatotropes, as suggested by Cogan et al. (1995).
In 2 unrelated kindreds with autosomal dominant growth hormone deficiency (IGHD2; 173100), Cogan et al. (1997) reported 2 intron-3 mutations in the GH1 gene. These mutations perturbed splicing and caused exon 3 skipping; however, the mutations did not occur within the intron 3 branch consensus sites or the 5-prime or 3-prime splice sites. Instead, these mutations deranged sequences homologous to XGGG repeats that regulate alternative mRNA splicing in other genes. Eukaryotic pre-mRNA splicing is regulated by consensus sequences at the intron boundaries and branch site. Sirand-Pugnet et al. (1995) demonstrated the importance of an additional intronic sequence, an (A/U)GGG repeat in chicken beta-tropomyocin that is a binding site for a protein required for spliceosome assembly. The mutations found by Cogan et al. (1997) in the third intron of the GH gene affected a putative, homologous consensus sequence and disturbed splicing. The first mutation was a G-to-A transition base 28 of intron 3 and the second deleted 18 bp (del+28-45; 139250.0012) of intron 3 of the human GH gene. The findings suggested that XGGG repeats may regulate alternative splicing in the human growth hormone gene and that mutations of these repeats cause growth hormone deficiency by perturbing alternative splicing.
For discussion of the 18-bp deletion in the GH1 gene (del+28-45) that was found in compound heterozygous state in 2 unrelated kindreds with autosomal dominant growth hormone deficiency (IGHD2; 173100) by Cogan et al. (1997), see 139250.0011.
McCarthy and Phillips (1998) presented evidence that this mutation and the G-to-A transition at position +28 of IVS3 (139250.0011) disturb an intron splice enhancer (ISE) that is critical for the proper splicing of transcripts of the GH1 gene.
In a child presenting with short stature, Takahashi et al. (1997) demonstrated a biologically inactive growth hormone (see Kowarski syndrome, 262650) resulting from a heterozygous single-base substitution (A to G) in exon 4 of the GH1 gene. This change resulted in an asp112-to-gly (D112G) amino acid substitution. At age 3 years, the girl's height was 3.6 standard deviations below the mean for age and sex. Bone age was delayed by 1.5 years. She had a prominent forehead and a hypoplastic nasal bridge with normal body proportions. She showed lack of growth hormone action despite high immunoassayable GH levels in serum and marked catch-up growth to exogenous GH administration. Results of other studies were compatible with the production of a bioinactive GH, which prevented dimerization of the growth hormone receptor, a crucial step in GH signal transduction.
In a father and his 2 daughters with autosomal dominant isolated growth hormone deficiency (IGHD2; 173100), Kamijo et al. (1999) found a G-to-A transition at the fifth base of intron 3 of the GH1 gene. The paternal grandparents did not show the mutation, indicating that it was a new mutation in the case of the father. Kamijo et al. (1999) studied 2 other (sporadic) cases of IGHD II. It is curious and undoubtedly significant that so many mutations have been found in the splice donor site of IVS3 in cases of isolated growth hormone deficiency type II.
See also 139250.0009 and Hayashi et al. (1999).
Abdul-Latif et al. (2000) identified an extended, highly inbred Bedouin kindred with isolated growth hormone deficiency that clinically fulfilled the criteria for type IB (IGHD1B; 612781). Molecular studies demonstrated a novel mutation in the GH1 gene: a G-to-C transversion of the fifth base of intron 4, which appeared to cause GH deficiency through the use of a cryptic splice site and, consequently, formation of a different protein. Clinical observations suggested that apparently healthy, non-GH-deficient individuals in this family were of relatively short stature. Leiberman et al. (2000) correlated height measurements of potential heterozygotes with carrier status for the newly identified mutation. Indeed, they found that carriers of the mutant allele in heterozygous state had significantly shorter stature than normal homozygotes. They found that 11 of 33 (33%) of heterozygotes, but only 1 of 17 (5.9%) of normal homozygotes had their height at 2 or more standard deviations below the mean. Overall, 48.5% of studied heterozygotes were found to be of appreciably short stature with height at or lower than the 5th centile, whereas only 5.9% of the normal homozygotes fell into that range (P less than 0.004).
Moseley et al. (2002) reported an A-to-G transition of the fifth base of exon 3 (exon 3+5A-G) in affected individuals from an isolated growth hormone deficiency type II (IGHD2; 173100) family. This mutation disrupts a (GAA)n exon splice enhancer (ESE) motif immediately following the weak IVS2 3-prime splice site. The mutation also destroys a MboII site used to demonstrate heterozygosity in all affected family members. To determine the effect of ESE mutations on GH mRNA processing, GH3 cells were transfected with expression constructs containing the normal ESE, +5A-G, or other ESE mutations, and cDNAs derived from the resulting GH mRNAs were sequenced. All ESE mutations studied reduced activation of the IVS2 3-prime splice site and caused either partial exon 3 skipping, due to activation of an exon 3 +45 cryptic 3-prime splice site, or complete exon 3 skipping. Partial or complete exon 3 skipping led to loss of the codons for amino acids 32-46 or 32-71, respectively, of the mature GH protein. They concluded that the exon 3 +5A-G mutation causes IGHD II because it perturbs an ESE required for GH splicing.
In affected members of a Japanese family with autosomal dominant isolated growth hormone deficiency (IGHD2; 173100), Takahashi et al. (2002) found a heterozygous G-to-T transversion at the first 5-prime site nucleotide of exon 3. Analysis of the GH1 cDNA, synthesized from lymphoblasts of the patients, revealed an abnormally short transcript as well as a normal-sized transcript. Direct sequencing of the abnormal transcript showed that it completely lacked exon 3. In IGHD II, several heterozygous mutations have been reported at the donor splice site in intron 3 of the GH1 gene or inside intron 3 (e.g., 139250.0007, 139250.0009, 139250.0010), which cause aberrant growth hormone mRNA splicing, resulting in the deletion of exon 3. Loss of exon 3 results in lack of amino acid residues 32 to 71 in the mature growth hormone protein. This mutant growth hormone exerts a dominant-negative effect on the secretion of mature normal growth hormone protein. Thus, in the family reported by Takahashi et al. (2002), the G-to-T transversion at the first nucleotide resulted in deletion of exon 3 and caused growth hormone deficiency. Takahashi et al. (2002) suggested that the first nucleotide of exon 3 is critical for the splicing of GH1 mRNA.
Fofanova et al. (2003) studied mutations in 28 children from 26 families with total isolated growth hormone deficiency (IGHD) living in Russia. They found 3 dominant-negative mutations causing IGHD type II (IGHD2; 173100): (1) an A-to-T transversion of the second base of the 3-prime acceptor splice site of intron 2 (IVS2-2A-T); (2) a T-to-C transition of the second base of the 5-prime donor splice site of intron 3 (IVS3+2T-C; 139250.0019); and (3) a G-to-A transition of the first base of the 5-prime donor splice site of intron 3 (IVS3+1G-A; 139250.0009). The IVS-2A-T mutation was the first identified mutation in intron 2 of GH1. The authors concluded that the 5-prime donor splice site of intron 3 of GH1 is a mutation hotspot, and the IVS3+1G-A mutation can be considered to be a common molecular defect in IGHD2 in Russian patients.
For discussion of the splice site mutation in the GH1 gene (IVS3+2T-C) that was found in children with isolated growth hormone deficiency type II (IGHD2; 173100) by Fofanova et al. (2003), see 139250.0018.
In a Serbian patient with short stature and bioinactive growth hormone (Kowarski syndrome; 262650) Besson et al. (2005) detected a homozygous cys53-to-ser (C53S) mutation in the GH1 gene. The mutation arose from a G-to-C transversion at nucleotide position 705 (G705C). The phenotypically normal first-cousin parents were heterozygous for the mutation. This mutation was predicted to lead to the absence of the disulfide bridge cys53 to cys165. In GH receptor (GHR; 600946) binding and Jak2 (147796)/Stat5 (601511) activation experiments, Besson et al. (2005) observed that at physiologic concentrations (3-50 ng/ml), both GHR binding and Jak2/Stat5 signaling pathway activation were significantly reduced in the mutant GH-C53S, compared with wildtype. Higher concentrations (400 ng/ml) were required for this mutant to elicit responses similar to wildtype GH. Besson et al. (2005) concluded that the absence of the disulfide bridge cys53 to cys165 affects the binding affinity of GH for the GHR and subsequently the potency of GH to activate the Jak2/Stat5 signaling pathway.
In a 2-year-old child and her mother with severe growth failure at diagnosis (IGHD2; 173100) (-5.8 and -6.9 SD score, respectively), Vivenza et al. (2006) identified a heterozygous 22-bp deletion in IVS3 of the GH1 gene, designated IVS3del+56-77, removing the putative branch point sequence (BPS). Both patients showed 2 principal mRNA species approximately in equal amount, i.e., a full-length species encoded by the normal allele, and an aberrant splicing product with the skipping of exon 3 encoded by the mutant allele. Their clinical phenotype correlated with that observed in other IGHD2 patients harboring splice site mutations.
In a large kindred with dominant growth hormone deficiency (IGHD2; 173100) Gertner et al. (1998) detected a heterozygous G-to-A transition at nucleotide 6664 in exon 5 of the GH1 gene, resulting in an arg183-to-his substitution (R183H).
Hess et al. (2007) studied the phenotype-genotype correlation of subjects with IGHD2 caused by an R183H mutation in the GH1 gene in 34 affected members of 2 large families. Twenty-four of the 52 members from family 1 and 10 of the 14 from family 2 carried the same mutation in a heterozygous state. The affected subjects in family 1 were significantly shorter (-2.6 vs -0.1 standard deviation score (SDS), p less than 0.0001) and had significantly lower IGF1 (147440) serum levels (-1.9 vs -0.5 SDS, p less than 0.0001), compared with family members with a normal genotype. The affected adults exhibited great variability in their stature, ranging from -4.5 to -1.0 SD (mean -2.8 SDS), with 5 members being of normal height (greater than -2 SDS). Twelve children were diagnosed with IGHD. Two affected children had normal peak GH levels, although 1 of these subsequently demonstrated GH insufficiency. The affected children from both families exhibited large variability in their height, growth velocity, delay in bone age, age at diagnosis, peak GH response, and IGF1 levels. Hess et al. (2007) concluded that these detailed phenotypic analyses show the variable expressivity of patients bearing the R183H mutation, reflecting the spectrum of GH deficiency in affected patients, even within families, and the presence of additional genes modifying height determination.
In 2 independent pedigrees with isolated growth hormone deficiency type II (IGHD2; 173100), Petkovic et al. (2007) identified a heterozygous splice enhancer mutation in exon 3, exon 3+2A-C, that encodes a glutamic acid-to-alanine change at position 32 in the GH protein (E32A) and leads to missplicing at the mRNA level, producing large amounts of the 17.5-kD GH isoform. Mouse pituitary cells coexpressing both wildtype and mutant GH-E32A protein presented a significant reduction in cell proliferation as well as GH production after forskolin stimulation when compared with the cells expressing wildtype GH. These results were complemented with confocal microscopy analysis, which revealed a significant reduction of the GH-E32A-derived isoform colocalized with secretory granules, compared with wildtype GH. Petkovic et al. (2007) concluded that the GH-E32A mutation, which occurred in the exon splice enhancer (ESE1), weakens recognition of exon 3 directly, and therefore increases production of the exon 3-skipped 17.5-kD GH isoform in relation to the 22-kD, wildtype GH isoform.
In affected members of a 4-generation family segregating autosomal dominant growth hormone deficiency (IGHD2; 173100), Shariat et al. (2008) identified heterozygosity for a +1G-A transition in exon 3 of the GH gene. The change was predicted to encode a glu32-to-lys (E32K) substitution; however, transfection studies showed that when the mutant was expressed, there was an approximately 6-fold increase in skipping of exon 3 compared to wildtype (39% and 6%, respectively). Functional analysis revealed that the variant weakens the 3-prime splice site and simultaneously disrupts a splicing enhancer located within the first 7 bases of exon 3.
Abdul-Latif, H., Leiberman, E., Brown, M. R., Carmi, R., Parks, J. S. Growth hormone deficiency type IB caused by cryptic splicing of the GH-1 gene. J. Pediat. Endocr. Metab. 13: 21-28, 2000. [PubMed: 10689634] [Full Text: https://doi.org/10.1515/jpem.2000.13.1.21]
Akinci, A., Kanaka, C., Eble, A., Akar, N., Vidinlisan, S., Mullis, P. E. Isolated growth hormone (GH) deficiency type IA associated with a 45-kilobase gene deletion within the human GH gene cluster. J. Clin. Endocr. Metab. 75: 437-441, 1992. [PubMed: 1322425] [Full Text: https://doi.org/10.1210/jcem.75.2.1322425]
Baxter, J. D., Seeburg, P. H., Shine, J., Martial, J. A., Goodman, H. M. The gene for growth hormone (GH): DNA sequence, expression, regulation. (Abstract) Clin. Res. 25: 461A, 1977.
Baxter, J. D. Personal Communication. San Francisco, Calif. 4/1981.
Behncken, S. N., Rowlinson, S. W., Rowland, J. E., Conway-Campbell, B. L., Monks, T. A., Waters, M. J. Aspartate 171 is the major primate-specific determinant of human growth hormone. J. Biol. Chem. 272: 27077-27083, 1997. [PubMed: 9341147] [Full Text: https://doi.org/10.1074/jbc.272.43.27077]
Besson, A., Salemi, S., Deladoey, J., Vuissoz, J.-M., Eble, A., Bidlingmaier, M., Burgi, S., Honegger, U., Fluck, C., Mullis, P. E. Short stature caused by a biologically inactive mutant growth hormone (GH-C53S). J. Clin. Endocr. Metab. 90: 2493-2499, 2005. [PubMed: 15713716] [Full Text: https://doi.org/10.1210/jc.2004-1838]
Binder, G., Brown, M., Parks, J. S. Mechanisms responsible for dominant expression of human growth hormone gene mutations. J. Clin. Endocr. Metab. 81: 4047-4050, 1996. [PubMed: 8923859] [Full Text: https://doi.org/10.1210/jcem.81.11.8923859]
Binder, G., Ranke, M. B. Screening for growth hormone (GH) gene splice-site mutations in sporadic cases with severe isolated GH deficiency using ectopic transcript analysis. J. Clin. Endocr. Metab. 80: 1247-1252, 1995. [PubMed: 7714096] [Full Text: https://doi.org/10.1210/jcem.80.4.7714096]
Boguszewski, C. L., Jansson, C., Boguszewski, M. C. S., Rosberg, S., Carlsson, B., Albertsson-Wikland, K., Carlsson, L. M. S. Increased proportion of circulating non-22-kilodalton growth hormone isoforms in short children: a possible mechanism for growth failure. J. Clin. Endocr. Metab. 82: 2944-2949, 1997. [PubMed: 9284724] [Full Text: https://doi.org/10.1210/jcem.82.9.4226]
Braga, S., Phillips, J. A., III, Joss, E., Schwarz, H., Zuppinger, K. Familial growth hormone deficiency resulting from a 7.6 kb deletion within the growth hormone gene cluster. Am. J. Med. Genet. 25: 443-452, 1986. [PubMed: 3024485] [Full Text: https://doi.org/10.1002/ajmg.1320250306]
Chakravarti, A., Phillips, J. A., III, Mellits, K. H., Buetow, K. H., Seeburg, P. H. Patterns of polymorphism and linkage disequilibrium suggest independent origins of the human growth hormone gene cluster. Proc. Nat. Acad. Sci. 81: 6085-6089, 1984. [PubMed: 6091133] [Full Text: https://doi.org/10.1073/pnas.81.19.6085]
Chen, E. Y., Liao, Y.-C., Smith, D. H., Barrera-Saldana, H. A., Gelinas, R. E., Seeburg, P. H. The human growth hormone locus: nucleotide sequence, biology, and evolution. Genomics 4: 479-497, 1989. [PubMed: 2744760] [Full Text: https://doi.org/10.1016/0888-7543(89)90271-1]
Cogan, J. D., Phillips, J. A., III, Sakati, N., Frisch, H., Schober, E., Milner, R. D. G. Heterogeneous growth hormone (GH) gene mutations in familial GH deficiency. J. Clin. Endocr. Metab. 76: 1224-1228, 1993. [PubMed: 8496314] [Full Text: https://doi.org/10.1210/jcem.76.5.8496314]
Cogan, J. D., Prince, M. A., Lekhakula, S., Bundey, S., Futrakul, A., McCarthy, E. M. S., Phillips, J. A., III. A novel mechanism of aberrant pre-mRNA splicing in humans. Hum. Molec. Genet. 6: 909-912, 1997. [PubMed: 9175738] [Full Text: https://doi.org/10.1093/hmg/6.6.909]
Cogan, J. D., Ramel, B., Lehto, M., Phillips, J., III, Prince, M., Blizzard, R. M., de Ravel, T. J. L., Brammert, M., Groop, L. A recurring dominant negative mutation causes autosomal dominant growth hormone deficiency: a clinical research center study. J. Clin. Endocr. Metab. 80: 3591-3595, 1995. [PubMed: 8530604] [Full Text: https://doi.org/10.1210/jcem.80.12.8530604]
Cooke, N. E., Szpirer, C., Levan, G. The related genes encoding growth hormone and prolactin have been dispersed to chromosomes 10 and 17 in the rat. Endocrinology 119: 2451-2454, 1986. [PubMed: 3780533] [Full Text: https://doi.org/10.1210/endo-119-6-2451]
Dayhoff, M. O. Atlas of Protein Sequence and Structure. Hormones, active peptides and toxins. Vol. 5. Washington: Biomedical Research Foundation (pub.) 1972. P. D202.
De Groof, F., Joosten, K. F. M., Janssen, J. A. M. J. L., De Kleijn, E. D., Hazelzet, J. A., Hop, W. C. J., Uitterlinden, P., Van Doorn, J., Hokken-Koelega, A. C. S. Acute stress response in children with meningococcal sepsis: important differences in the growth hormone/insulin-like growth factor I axis between nonsurvivors and survivors. J. Clin. Endocr. Metab. 87: 3118-3124, 2002. [PubMed: 12107211] [Full Text: https://doi.org/10.1210/jcem.87.7.8605]
Dennison, E. M., Syddall, H. E., Rodriguez, S., Voropanov, A., Day, I. N. M., Cooper, C., Southampton Genetic Epidemiology Research Group. Polymorphism in the growth hormone gene, weight in infancy, and adult bone mass. J. Clin. Endocr. Metab. 89: 4898-4903, 2004. [PubMed: 15472182] [Full Text: https://doi.org/10.1210/jc.2004-0151]
Duquesnoy, P., Amselem, S., Gourmelen, M., LeBouc, Y., Goossens, M. A frameshift mutation causing isolated growth hormone deficiency type 1A. (Abstract) Am. J. Hum. Genet. 47: A110, 1990.
Fiddes, J. C., Seeburg, P. H., DeNoto, F. M., Hallewell, R. A., Baxter, J. D., Goodman, H. M. Structure of genes for human growth hormone and chorionic somatomammotropin. Proc. Nat. Acad. Sci. 76: 4294-4298, 1979. [PubMed: 291965] [Full Text: https://doi.org/10.1073/pnas.76.9.4294]
Fofanova, O. V., Evgrafov, O. V., Polyakov, A. V., Poltaraus, A. B., Peterkova, V. A., Dedov, I. I. A novel IVS2 -2A-T splicing mutation in the GH-1 gene in familial isolated growth hormone deficiency type II in the spectrum of other splicing mutations in the Russian population. J. Clin. Endocr. Metab. 88: 820-826, 2003. [PubMed: 12574219] [Full Text: https://doi.org/10.1210/jc.2002-020269]
Ge, G., Fernandez, C. A., Moses, M. A., Greenspan, D. S. Bone morphogenetic protein 1 processes prolactin to a 17-kDa antiangiogenic factor. Proc. Nat. Acad. Sci. 104: 10010-10015, 2007. [PubMed: 17548836] [Full Text: https://doi.org/10.1073/pnas.0704179104]
Geary, M. P. P., Pringle, P. J., Rodeck, C. H., Kingdom, J. C. P., Hindmarsh, P. C. Sexual dimorphism in the growth hormone and insulin-like growth factor axis at birth. J. Clin. Endocr. Metab. 88: 3708-3714, 2003. [PubMed: 12915659] [Full Text: https://doi.org/10.1210/jc.2002-022006]
George, D. L., Phillips, J. A., III, Francke, U., Seeburg, P. H. The genes for growth hormone and chorionic somatomammotropin are on the long arm of human chromosome 17 in region q21-to-qter. Hum. Genet. 57: 138-141, 1981. [PubMed: 6262212] [Full Text: https://doi.org/10.1007/BF00282009]
Gertner, J. M., Wajnrajch, M. P., Leibel, R. L. Genetic defects in the control of growth hormone secretion. Horm. Res. 49: 9-14, 1998. [PubMed: 9554464] [Full Text: https://doi.org/10.1159/000053062]
Giordano, M., Godi, M., Mellone, S., Petri, A., Vivenza, D., Tiradani, L., Carlomagno, Y., Ferrante, D., Arrigo, T., Corneli, G., Bellone, S., Giacopelli, F., Santoro, C., Bona, G., Momigliano-Richiardi, P. A functional common polymorphism in the vitamin D-responsive element of the GH1 promoter contributes to isolated growth hormone deficiency. J. Clin. Endocr. Metab. 93: 1005-1012, 2008. [PubMed: 18160466] [Full Text: https://doi.org/10.1210/jc.2007-1918]
Goossens, M., Brauner, R., Czernichow, P., Duquesnoy, P., Rappaport, R. Isolated growth hormone (GH) deficiency type 1A associated with a double deletion in the human GH gene cluster. J. Clin. Endocr. Metab. 62: 712-716, 1986. [PubMed: 3005356] [Full Text: https://doi.org/10.1210/jcem-62-4-712]
Greenhalgh, C. J., Rico-Bautista, E., Lorentzon, M., Thaus, A. L., Morgan, P. O., Willson, T. A., Zervoudakis, P., Metcalf, D., Street, I., Nicola, N. A., Nash, A. D., Fabri, L. J., Norstedt, G., Ohlsson, C., Flores-Morales, A., Alexander, W. S., Hilton, D. J. SOCS2 negatively regulates growth hormone action in vitro and in vivo. J. Clin. Invest. 115: 397-406, 2005. [PubMed: 15690087] [Full Text: https://doi.org/10.1172/JCI22710]
Grumbach, M. M. Personal Communication. San Francisco, Calif. 1981.
Harper, M. E., Barrera-Saldana, H. A., Saunders, G. F. Chromosomal localization of the human placental lactogen-growth hormone gene cluster to 17q22-24. Am. J. Hum. Genet. 34: 227-234, 1982. [PubMed: 7072716]
Hasegawa, Y., Fujii, K., Yamada, M., Igarashi, Y., Tachibana, K., Tanaka, T., Onigata, K., Nishi, Y., Kato, S., Hasegawa, T. Identification of novel human GH-1 gene polymorphisms that are associated with growth hormone secretion and height. J. Clin. Endocr. Metab. 85: 1290-1295, 2000. [PubMed: 10720078] [Full Text: https://doi.org/10.1210/jcem.85.3.6468]
Hayashi, Y., Yamamoto, M., Ohmori, S., Kamijo, T., Ogawa, M., Seo, H. Inhibition of growth hormone (GH) secretion by a mutant GH-I gene product in neuroendocrine cells containing secretory granules: an implication for isolated GH deficiency inherited in an autosomal dominant manner. J. Clin. Endocr. Metab. 84: 2134-2139, 1999. [PubMed: 10372722] [Full Text: https://doi.org/10.1210/jcem.84.6.5736]
He, Y. A., Chen, S. S., Wang, Y. X., Lin, X. Y., Wang, D. F. A Chinese familial growth hormone deficiency with a deletion of 7.1 kb of DNA. J. Med. Genet. 27: 151-154, 1990. [PubMed: 2325087] [Full Text: https://doi.org/10.1136/jmg.27.3.151]
Hess, O., Hujeirat, Y., Wajnrajch, M. P., Allon-Shalev, S., Zadik, Z., Lavi, I., Tenenbaum-Rakover, Y. Variable phenotypes in familial isolated growth hormone deficiency caused by a G6664A mutation in the GH-1 gene. J. Clin. Endocr. Metab. 92: 4387-4393, 2007. [PubMed: 17785368] [Full Text: https://doi.org/10.1210/jc.2007-0684]
Hindmarsh, P. C., Dennison, E., Pincus, S. M., Cooper, C., Fall, C. H. D., Matthews, D. R., Pringle, P. J., Brook, C. G. D. A sexually dimorphic pattern of growth hormone secretion in the elderly. J. Clin. Endocr. Metab. 84: 2679-2685, 1999. [PubMed: 10443659] [Full Text: https://doi.org/10.1210/jcem.84.8.5915]
Ho, Y., Elefant, F., Cooke, N., Liebhaber, S. A defined locus control region determinant links chromatin domain acetylation with long-range gene activation. Molec. Cell 9: 291-302, 2002. [PubMed: 11864603] [Full Text: https://doi.org/10.1016/s1097-2765(02)00447-1]
Ho, Y., Elefant, F., Liebhaber, S. A., Cooke, N. E. Locus control region transcription plays an active role in long-range gene activation. Molec. Cell 23: 365-375, 2006. Note: Erratum: Molec. Cell 23: 619 only, 2006. [PubMed: 16885026] [Full Text: https://doi.org/10.1016/j.molcel.2006.05.041]
Horan, M., Millar, D. S., Hedderich, J., Lewis, G., Newsway, V., Mo, N., Fryklund, L., Procter, A. M., Krawczak, M., Cooper, D. N. Human growth hormone 1 (GH1) gene expression: complex haplotype-dependent influence of polymorphic variation in the proximal promoter and locus control region. Hum. Mutat. 21: 408-423, 2003. [PubMed: 12655556] [Full Text: https://doi.org/10.1002/humu.10167]
Horan, M., Newsway, V., Yasmin, (NI), Lewis, M. D., Easter, T. E., Rees, D. A., Mahto, A., Millar, D. S., Procter, A. M., Scanlon, M. F., Wilkinson, I. B., Hall, I. P., Wheatley, A., Blakey, J., Bath, P. M. W., Cockcroft, J. R., Krawczak, M., Cooper, D. N. Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke. Hum. Genet. 119: 527-540, 2006. [PubMed: 16572267] [Full Text: https://doi.org/10.1007/s00439-006-0166-5]
Igarashi, Y., Ogawa, M., Kamijo, T., Iwatani, N., Nishi, Y., Kohno, H., Masumura, T., Koga, J. A new mutation causing inherited growth hormone deficiency: a compound heterozygote of a 6.7 kb deletion and a two base deletion in the third exon of the GH-1 gene. Hum. Molec. Genet. 2: 1073-1074, 1993. [PubMed: 8364549] [Full Text: https://doi.org/10.1093/hmg/2.7.1073]
Jones, B. K., Monks, B. R., Liebhaber, S. A., Cooke, N. E. The human growth hormone gene is regulated by a multicomponent locus control region. Molec. Cell. Biol. 15: 7010-7021, 1995. [PubMed: 8524268] [Full Text: https://doi.org/10.1128/MCB.15.12.7010]
Kamijo, T., Hayashi, Y., Shimatsu, A., Kinoshita, E., Yoshimoto, M., Ogawa, M., Seo, H. Mutations in intron 3 of GH-1 gene associated with isolated GH deficiency type II in three Japanese families. Clin. Endocr. 51: 355-360, 1999. [PubMed: 10469016] [Full Text: https://doi.org/10.1046/j.1365-2265.1999.00798.x]
Lebo, R. V. Personal Communication. San Francisco, Calif. 7/31/1980.
Leiberman, E., Pesler, D., Parvari, R., Elbedour, K., Abdul-Latif, H., Brown, M. R., Parks, J. S., Carmi, R. Short stature in carriers of recessive mutation causing familial isolated growth hormone deficiency. Am. J. Med. Genet. 90: 188-192, 2000. [PubMed: 10678654]
Lewis, M. D., Horan, M., Millar, D. S., Newsway, V., Easter, T. E., Fryklund, L., Gregory, J. W., Norin, M., Del Valle, C.-J., Lopez-Siguero, J. P., Canete, R., Lopez-Canti, L. F., Diaz-Torrado, N., Espino, R., Ulied, A., Scanlon, M. F., Procter, A. M., Cooper, D. N. A novel dysfunctional growth hormone variant (ile179met) exhibits a decreased ability to activate the extracellular signal-regulated kinase pathway. J. Clin. Endocr. Metab. 89: 1068-1075, 2004. [PubMed: 15001589] [Full Text: https://doi.org/10.1210/jc.2003-030652]
Martial, J. A., Hallewell, R. A., Baxter, J. D., Goodman, H. M. Human growth hormone: complementary DNA cloning and expression in bacteria. Science 205: 602-607, 1979. [PubMed: 377496] [Full Text: https://doi.org/10.1126/science.377496]
Masuda, N., Watahiki, M., Tanaka, M., Yamakawa, M., Shimizu, K., Nagai, J., Nakashima, K. Molecular cloning of cDNA encoding 20 kDa variant human growth hormone and the alternative splicing mechanism. Biochim. Biophys. Acta 949: 125-131, 1988. [PubMed: 2825811] [Full Text: https://doi.org/10.1016/0167-4781(88)90062-0]
McCarthy, E. M. S., Phillips, J. A., III. Characterization of an intron splice enhancer that regulates alternative splicing of human GH pre-mRNA. Hum. Molec. Genet. 7: 1491-1496, 1998. [PubMed: 9700205] [Full Text: https://doi.org/10.1093/hmg/7.9.1491]
Mendlewicz, J., Linkowski, P., Kerkhofs, M., Leproult, R., Copinschi, G., Van Cauter, E. Genetic control of 24-hour growth hormone secretion in man: a twin study. J. Clin. Endocr. Metab. 84: 856-862, 1999. [PubMed: 10084561] [Full Text: https://doi.org/10.1210/jcem.84.3.5525]
Millar, D. S., Lewis, M. D., Horan, M., Newsway, V., Easter, T. E., Gregory, J. W., Fryklund, L., Norin, M., Crowne, E. C., Davies, S. J., Edwards, P., Kirk, J., Waldron, K., Smith, P. J., Phillips, J. A., III, Scanlon, M. F., Krawczak, M., Cooper, D. N., Procter, A. M. Novel mutations of the growth hormone 1 (GH1) gene disclosed by modulation of the clinical selection criteria for individuals with short stature. Hum. Mutat. 21: 424-440, 2003. [PubMed: 12655557] [Full Text: https://doi.org/10.1002/humu.10168]
Morgan, J. R., Barrandon, Y., Green, H., Mulligan, R. C. Expression of an exogenous growth hormone gene by transplantable human epidermal cells. Science 237: 1476-1479, 1987. [PubMed: 3629250] [Full Text: https://doi.org/10.1126/science.3629250]
Moseley, C. T., Mullis, P. E., Prince, M. A., Phillips, J. A., III. An exon splice enhancer mutation causes autosomal dominant GH deficiency. J. Clin. Endocr. Metab. 87: 847-852, 2002. [PubMed: 11836331] [Full Text: https://doi.org/10.1210/jcem.87.2.8236]
Mullis, P. E., Akinci, A., Kanaka, C., Eble, A., Brook, C. G. D. Prevalence of human growth hormone-1 gene deletions among patients with isolated growth hormone deficiency from different populations. Pediat. Res. 31: 532-534, 1992. [PubMed: 1603635] [Full Text: https://doi.org/10.1203/00006450-199205000-00026]
Mullis, P. E., Robinson, I. C. A. F., Salemi, S., Eble, A., Besson, A., Vuissoz, J.-M., Deladoey, J., Simon, D., Czernichow, P., Binder, G. Isolated autosomal dominant growth hormone deficiency: an evolving pituitary deficit? A multicenter follow-up study. J. Clin. Endocr. Metab. 90: 2089-2096, 2005. [PubMed: 15671105] [Full Text: https://doi.org/10.1210/jc.2004-1280]
Niall, H. D., Hogan, M. L., Sauer, R., Rosenblum, I. Y., Greenwood, F. C. Sequence of pituitary and placental lactogenic and growth hormones: evolution from a primordial peptide by gene reduplication. Proc. Nat. Acad. Sci. 68: 866-869, 1971. [PubMed: 5279528] [Full Text: https://doi.org/10.1073/pnas.68.4.866]
Owerbach, D., Rutter, W. J., Martial, J. A., Baxter, J. D., Shows, T. B. Genes for growth hormone, chorionic somatomammotropin and growth hormone-like genes on chromosome 17 in humans. Science 209: 289-292, 1980. [PubMed: 7384802] [Full Text: https://doi.org/10.1126/science.7384802]
Paladini, A. C., Pena, C., Retegui, L. A. The intriguing nature of the multiple actions of growth hormone. Trends Biochem. Sci. 4: 256-260, 1979.
Petkovic, V., Besson, A., Thevis, M., Lochmatter, D., Eble, A., Fluck, C. E., Mullis, P. E. Evaluation of the biological activity of a growth hormone (GH) mutant (R77C) and its impact on GH responsiveness and stature. J. Clin. Endocr. Metab. 92: 2893-2901, 2007. [PubMed: 17519310] [Full Text: https://doi.org/10.1210/jc.2006-2238]
Petkovic, V., Lochmatter, D., Turton, J., Clayton, P. E., Trainer, P. J., Dattani, M. T., Eble, A., Robinson, I. C., Fluck, C. E., Mullis, P. E. Exon splice enhancer mutation (GH-E32A) causes autosomal dominant growth hormone deficiency. J. Clin. Endocr. Metab. 92: 4427-4435, 2007. [PubMed: 17726075] [Full Text: https://doi.org/10.1210/jc.2007-0857]
Phillips, J. A., III, Cogan, J. D. Genetic basis of endocrine disease 6: molecular basis of familial human growth hormone deficiency. J. Clin. Endocr. Metab. 78: 11-16, 1994. [PubMed: 8288694] [Full Text: https://doi.org/10.1210/jcem.78.1.8288694]
Phillips, J. A., III, Hjelle, B. L., Seeburg, P. H., Plotnick, L. P., Migeon, C. J., Zachmann, M. Heterogeneity in the molecular basis of familial growth hormone deficiency (IGHD). (Abstract) Am. J. Hum. Genet. 33: 52A, 1981.
Phillips, J. A., III. Personal Communication. Baltimore, Md. 1/17/1983.
Phillips, J. A., III. Inherited defects in growth hormone synthesis and action. In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.): The Metabolic and Molecular Bases of Inherited Disease. Vol. II. (7th ed.) New York: McGraw-Hill (pub.) 1995. Pp. 3023-3044.
Rimoin, D. L., Phillips, J. A., III. Genetic disorders of the pituitary gland. In: Rimoin, D. L.; Connor, J. M.; Pyeritz, R. E. (eds.): Principles and Practice of Medical Genetics. Vol. I. (3rd ed.) New York: Churchill Livingstone (pub.) 1997. Pp. 1331-1364.
Ruddle, F. H. Personal Communication. New Haven, Conn. 2/7/1982.
Ryther, R. C. C., McGuinness, L. M., Phillips, J. A., III, Moseley, C. T., Magoulas, C. B., Robinson, I. C. A. F., Patton, J. G. Disruption of exon definition produces a dominant-negative growth hormone isoform that causes somatotroph death and IGHD II. Hum. Genet. 113: 140-148, 2003. [PubMed: 12720086] [Full Text: https://doi.org/10.1007/s00439-003-0949-x]
Saitoh, H., Fukushima, T., Kamoda, T., Tanae, A., Kamijo, T., Yamamoto, M., Ogawa, M., Hayashi, Y., Ohmori, S., Seo, H. A Japanese family with autosomal dominant growth hormone deficiency. Europ. J. Pediat. 158: 624-627, 1999. [PubMed: 10445339] [Full Text: https://doi.org/10.1007/s004310051164]
Shariat, N., Holladay, C. D., Cleary, R. K., Phillips, J. A., III, Patton, J. G. Isolated growth hormone deficiency type II caused by a point mutation that alters both splice site strength and splicing enhancer function. Clin. Genet. 74: 539-545, 2008. [PubMed: 18554279] [Full Text: https://doi.org/10.1111/j.1399-0004.2008.01042.x]
Sirand-Pugnet, P., Durosay, P., Brody, E., Marie, J. An intronic (A/U)GGG repeat enhances the splicing of an alternative intron of the chicken beta-tropomyosin pre-mRNA. Nucleic Acids Res. 23: 3501-3507, 1995. [PubMed: 7567462] [Full Text: https://doi.org/10.1093/nar/23.17.3501]
Smith, L. E. H., Kopchick, J. J., Chen, W., Knapp, J., Kinose, F., Daley, D., Foley, E., Smith, R. G., Schaeffer, J. M. Essential role of growth hormone in ischemia-induced retinal neovascularization. Science 276: 1706-1709, 1997. [PubMed: 9180082] [Full Text: https://doi.org/10.1126/science.276.5319.1706]
Sundstrom, M., Lundqvist, T., Rodin, J., Giebel, L. B., Milligan, D., Norstedt, G. Crystal structure of an antagonist mutant of human growth hormone, G120R, in complex with its receptor at 2.9 angstrom resolution. J. Biol. Chem. 271: 32197-32203, 1996. [PubMed: 8943276] [Full Text: https://doi.org/10.1074/jbc.271.50.32197]
Takahashi, I., Takahashi, T., Komatsu, M., Sato, T., Takada, G. An exonic mutation of the GH-1 gene causing familial isolated growth hormone deficiency type II. Clin. Genet. 61: 222-225, 2002. [PubMed: 12000366] [Full Text: https://doi.org/10.1034/j.1399-0004.2002.610310.x]
Takahashi, Y., Kaji, H., Okimura, Y., Goji, K., Abe, H., Chihara, K. Short stature caused by a mutant growth hormone. New Eng. J. Med. 334: 432-436, 1996. Note: Erratum: New Eng. J. Med. 334: 1207 only, 1996. [PubMed: 8552145] [Full Text: https://doi.org/10.1056/NEJM199602153340704]
Takahashi, Y., Shirono, H., Arisaka, O., Takahashi, K., Yagi, T., Koga, J., Kaji, H., Okimura, Y., Abe, H., Tanaka, T., Chihara, K. Biologically inactive growth hormone caused by an amino acid substitution. J. Clin. Invest. 100: 1159-1165, 1997. [PubMed: 9276733] [Full Text: https://doi.org/10.1172/JCI119627]
Vivenza, D., Guazzarotti, L., Godi, M., Frasca, D., di Natale, B., Momigliano-Richiardi, P., Bona, G., Giordano, M. A novel deletion in the GH1 gene including the IVS3 branch site responsible for autosomal dominant isolated growth hormone deficiency. J. Clin. Endocr. Metab. 91: 980-986, 2006. [PubMed: 16368751] [Full Text: https://doi.org/10.1210/jc.2005-1703]
Vnencak-Jones, C. L., Phillips, J. A., III, Chen, E. Y., Seeburg, P. H. Molecular basis of human growth hormone gene deletions. Proc. Nat. Acad. Sci. 85: 5615-5619, 1988. [PubMed: 2840669] [Full Text: https://doi.org/10.1073/pnas.85.15.5615]
Vnencak-Jones, C. L., Phillips, J. A., III, Wang, D.-F. Use of polymerase chain reaction in detection of growth hormone gene deletions. J. Clin. Endocr. Metab. 70: 1550-1553, 1990. [PubMed: 2347891] [Full Text: https://doi.org/10.1210/jcem-70-6-1550]
Wolfrum, C., Shih, D. Q., Kuwajima, S., Norris, A. W., Kahn, C. R., Stoffel, M. Role of Foxa-2 in adipocyte metabolism and differentiation. J. Clin. Invest. 112: 345-356, 2003. [PubMed: 12865419] [Full Text: https://doi.org/10.1172/JCI18698]
Xu, W., Gorman, P. A., Rider, S. H., Hedge, P. J., Moore, G., Prichard, C., Sheer, D., Solomon, E. Construction of a genetic map of human chromosome 17 by use of chromosome-mediated gene transfer. Proc. Nat. Acad. Sci. 85: 8563-8567, 1988. [PubMed: 3186746] [Full Text: https://doi.org/10.1073/pnas.85.22.8563]
Yoo, E. J., Cajiao, I., Kim, J.-S., Kimura, A. P., Zhang, A., Cooke, N. E., Liebhaber, S. A. Tissue-specific chromatin modifications at a multigene locus generate asymmetric transcriptional interactions. Molec. Cell. Biol. 26: 5569-5579, 2006. [PubMed: 16847312] [Full Text: https://doi.org/10.1128/MCB.00405-06]