Alternative titles; symbols
HGNC Approved Gene Symbol: PTH1R
SNOMEDCT: 1231153007, 24629003, 720863002;
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38): 3:46,877,721-46,903,799 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | Chondrodysplasia, Blomstrand type | 215045 | Autosomal recessive | 3 |
| Eiken syndrome | 600002 | Autosomal recessive | 3 | |
| Failure of tooth eruption, primary | 125350 | Autosomal dominant | 3 | |
| Metaphyseal chondrodysplasia, Murk Jansen type | 156400 | Autosomal dominant | 3 |
The PTH1R gene encodes a receptor for both parathyroid hormone (PTH; 168450) and parathyroid hormone-related protein (PTHLH; 168470) (Juppner et al., 1991).
By COS-7 expression using an opossum kidney cell cDNA library, Juppner et al. (1991) cloned the cDNA encoding a 585-amino acid receptor for parathyroid hormone and for parathyroid hormone-related protein. The molecule has 7 potential membrane-spanning domains. The expressed receptor bound PTH and PTHLH with equal affinity, and both ligands equivalently stimulated adenylate cyclase. A striking homology with the calcitonin receptor and the secretin receptor and a lack of homology with other G protein-linked receptors indicated that these are related and represent a new family. Schipani et al. (1993) cloned identical cDNAs encoding the PTH/PTHRP receptor from the 2 major target organs for PTH, bone and kidney.
Juppner (1994) pointed out that PTHR is a member of a family of G protein-coupled receptors that includes receptors for secretin (182098), growth hormone-releasing hormone (139191), vasoactive intestinal polypeptide, type 1 (192321), gastric-inhibitory polypeptide (137241), glucagon-like peptide 1 (138032), glucagon (138033), corticotropin-releasing factor (122561), and pituitary adenylate cyclase activating peptide 1 (102981).
McCuaig et al. (1994) isolated genomic clones containing the mouse PTHR gene, including 10 kb of the promoter region. The gene spans more than 32 kb and was divided into 15 exons, 8 of which contains the transmembrane domains. The PTHR exons containing the predicted membrane-spanning domains are heterogeneous in length, and 3 of the exon/intron boundaries fall within putative transmembrane sequences, suggesting that the exons did not arise from duplication events. This arrangement is closely related to that of the growth hormone-releasing hormone receptor gene, particularly in the transmembrane region, providing strong evidence that the 2 genes evolved from a common precursor.
Expression of PTHR1 in the mouse is controlled by at least 2 promoters. The downstream promoter (P2) is ubiquitously expressed, whereas expression of the upstream promoter (P1) is largely restricted to kidney. Bettoun et al. (1997) cloned and characterized the 5-prime end of the human PTHR1 gene and found that its organization is very similar to that of the mouse. Transcription initiation sites of human P1 and P2 promoters are in similar, but not identical, positions to those of the mouse gene.
By somatic cell hybrid analysis, Pausova et al. (1994) mapped the PTHR gene to chromosome 3 and, by isotopic in situ hybridization, refined the assignment to 3p22-p21.1. They showed that the homologous gene is located on mouse chromosome 9 and rat chromosome 8, which are known to be highly homologous to human chromosome 3. Gelbert et al. (1994) mapped the PTHR gene to the vicinity of the 3p21.3-p21.2 boundary by PCR analysis of human/rodent somatic cell hybrid panels using oligonucleotide primers designed to amplify a portion of the gene from genomic DNA.
Three promoters, P1, P2, and P3, regulate the expression of PTHR. The P3 promoter, proximal to the gene, seems to be turned on in many tissues and to be the most active of the 3 in the human adult kidney. P3 is also active in human osteoblastic SaOS-2 cells. To better understand the structure-to-function relationship of P3, Manen et al. (2000) assayed, in transiently transfected SaOS-2 cells, the expression of reporter gene constructs containing truncated P3 promoter fragments and substitution mutants. They localized cis-acting elements essential for P3 promoter activity and identified 2 key Sp1 binding sites. They also found in the 5-prime-untranslated exon U4, transcribed from promoter P3, an element that inhibits the expression of the receptor and is not promoter-specific. This study provided new insights into PTHR expression in human osteoblast-like cells.
Mahon et al. (2002) demonstrated that PTH1R binds to the sodium/hydrogen exchanger regulatory factors NHERF1 (604990) and NHERF2 (606553) through a PDZ-domain interaction in vitro and in PTH target cells. NHERF2 simultaneously binds phospholipase C-beta-1 and an atypical, carboxyl-terminal PDZ consensus motif, ETVM, of the PTH1R through PDZ1 and PDZ2, respectively. PTH treatment of cells that express the NHERF2-PTH1R complex markedly activated phospholipase C-beta and inhibits adenylylcyclase through stimulation of inhibitory G proteins (see 139310). NHERF-mediated assembly of PTH1R and phospholipase C-beta is a unique mechanism to regulate PTH signaling in cells and membranes of polarized cells that express NHERF, which may account for many tissue- and cell-specific actions of PTH/PTH-related protein (168470) and may also be relevant to signaling by many G protein-coupled receptors.
Using COS cells expressing rabbit Nherf1 and human PTH1R, Wang et al. (2008) found that Nherf1 inhibited PKA-dependent activation of Erk1 (MAPK3; 601795)/Erk2 (MAPK1; 176948) following PTH1R stimulation. Nherf1 interrupted this signaling pathway at the level of Braf (164757) by several mechanisms.
Nishimori et al. (2019) showed that Pth1r inhibited activity of Sik3 (614776), which controls chondrocyte hypertrophy, in mouse growth plate chondrocytes. Sik3 was the predominant SIK involved in regulating chondrocyte differentiation, but it was supported by Sik1 (605705) and Sik2 (608973). Deletion of Sik3 rescued the lethal phenotype caused by chondrocyte hypertrophy and mineralization in Pthrp -/- mice. Combined deletion of Sik2 and Sik3 in osteoblasts and osteocytes caused high bone mass with accelerated bone turnover, mimicking the high-turnover phenotype in mice with constitutive Pth1r activation in these cells. Genetic evidence suggested that class IIa histone deacetylases (e.g., HDAC4; 605314) were the downstream mediators of SIK action in growth plate and osteoblasts/osteocytes.
Zhao et al. (2019) reported the cryoelectron microscopy structure of human PTH1R bound to a long-acting PTH analog and stimulatory G protein. The bound peptide adopted an extended helix with its N terminus inserted deeply into the receptor transmembrane domain, leading to partial unwinding of the C terminus of transmembrane helix-6 and induction of a sharp kink at the middle of this helix to allow the receptor to couple with G protein. In contrast with a single transmembrane domain structure state, the extracellular domain adopted multiple conformations.
Murk Jansen Metaphyseal Chondrodysplasia
Schipani et al. (1995) speculated that the Murk Jansen type of metaphyseal chondrodysplasia (MCDJ; 156400) might be due to an activating mutation of the PTHR gene. Patients with that autosomal dominant disorder have abnormal growth plate maturation and laboratory findings that are indistinguishable from hyperparathyroidism, namely, hypercalcemia, hypophosphatemia, and increased renal excretion of phosphate, cAMP, and hydroxyproline, despite normal or undetectable levels of parathyroid hormone and parathyroid hormone-like hormone. Indeed, in a patient with this disorder, Schipani et al. (1995) reported that he and his colleagues had found an activating PTHR mutation, a heterozygous nucleotide change in codon 223 that caused a his223-to-arg substitution (168468.0001) in the first intracellular loop of the PTHR protein. COS-7 cells expressing the mutant PTHR revealed ligand-independent cAMP accumulation that was approximately 4-fold higher than that observed in cells expressing the wildtype PTH receptor.
Parfitt et al. (1996) described the clinical course and detailed studies of calcium and bone metabolism done in 1976 of a patient with Jansen disease (JD) and compared the results with those from the same studies of 6 typical patients with mild primary hyperparathyroidism. In the patient with JD, the hypercalcemia was of early onset; chronic and nonprogressive; refractory to the administration of phosphate, glucocorticoid, and calcitonin; and accompanied by suppressed PTH levels (determined by 2 different immunoassays), undetectable PTH-related peptide levels, and increased excretion of nephrogenous cAMP. Exaggerated loss of cortical bone and preservation of cancellous bone were noted. All the results in JD relating to renal or skeletal effects of PTH excess were within or close to the ranges found in the hyperparathyroid patients, except that tubular reabsorption of phosphate was more depressed. The authors concluded that (1) the hypercalcemia due to constitutive overactivity of the PTH/PTHRP receptor is indistinguishable from that of mild primary hyperparathyroidism in clinical characteristics as well as renal tubular and skeletal features; and (2) the classic laboratory manifestations of primary hyperparathyroidism, with the possible exception of osteitis fibrosa cystica, can all be accounted for by overactivity of a single receptor.
Blomstrand Chondrodysplasia
Jobert et al. (1998) demonstrated that mutational inactivation of PTH receptors (168468.0003) is responsible for Blomstrand chondrodysplasia (BOCD; 215045), a genetic disorder characterized by advanced endochondral bone maturation. The skeletal abnormalities in Blomstrand chondrodysplasia are the mirror image of those observed in Jansen chondrodysplasia.
In 2 cases of BOCD, including the first reported case (Blomstrand et al., 1985), Hoogendam et al. (2007) identified homozygosity for a nonsense mutation (168468.0010) and a splice site mutation (168468.0011) in the PTHR1 gene, respectively.
Eiken Syndrome
In a consanguineous Turkish family, Eiken et al. (1984) described 3 brothers with a skeletal dysplasia characterized by severely retarded ossification, principally of the epiphyses, pelvis, hands, and feet, as well as abnormal modeling of the bones. By linkage analysis with the original pedigree, Duchatelet et al. (2005) mapped Eiken syndrome (EKNS; 600002) to chromosome 3p near the PTHR1 gene. Affected individuals were homozygous for a nonsense mutation in the C-terminal cytoplasmic tail of the PTHR1 gene (R485X; 168468.0009).
In a 7-year-old boy with Eiken syndrome, who was born to unaffected first-cousin parents, Moirangthem et al. (2018) identified a homozygous missense mutation at a conserved residue in the PTHR1 gene (E35K; 168468.0015). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in his parents. The variant was not found in several public databases (ExAC, gnomAD, and 1000 Genomes Project) or in an in-house exome database of 417 families. Protein modeling predicted that the mutation would disrupt normal protein function.
In a 6-year-old Indian boy with Eiken syndrome, Jacob et al. (2019) identified homozygosity for a missense mutation in the PTH1R gene (Y134S; 168468.0016).
Primary Failure of Tooth Eruption
In affected members of 4 German families with nonsyndromic primary failure of tooth eruption (PFE; 125350), Decker et al. (2008) identified heterozygosity for 2 splice site and 1 nonsense mutation in the PTHR1 gene, respectively (168468.0001-168468.0003), that were not found in unaffected family members or 178 German controls. The mutations were predicted to result in premature proteolytic degradation of the precursor protein or a functionless receptor, suggesting that haploinsufficiency of PTHR1 is likely to be the underlying principle of nonsyndromic PFE. Decker et al. (2008) noted that PFE had not been reported as a symptom in heterozygous carriers of Blomstrand-type chondrodysplasia (BOCD; 215045) mutations, and suggested that this might be explained by incomplete medical histories of carrier parents of BOCD fetuses.
Other Associations
Minagawa et al. (2002) identified a tetranucleotide repeat (AAAG)n polymorphism in the P3 promoter of PTHR1. In 214 unrelated Japanese, the repeat number (n) ranged from 3 to 8, with the AAAG5 allele being the most frequent (59%). In 55 unrelated Caucasians, n ranged from 5 to 7, and the frequency of the AAAG5 allele was 78%. The most frequent genotypes in a cohort of 85 young (18 to 20 years) female Japanese were 5/5, 5/6, and 6/6. The 6/6 genotype was associated with greater height (5/5 vs 6/6; P less than 0.02) and lower urinary deoxypyridinoline and pyridinoline (P less than 0.02), which are markers of bone resorption. The height of an additional 71 healthy female Japanese subjects, aged 14 to 17 years, having genotype 5/5, 5/6, or 6/6 was also in the order of genotype 5/5, 5/6, 6/6 (5/5 vs 6/6, P less than 0.05). The activity of P3 promoter-luciferase reporter constructs in transcription assays in 2 human osteoblast-like cell lines varied according to repeat number, with AAAG6 being the least active.
Scillitani et al. (2006) evaluated the association of the (AAAG)n polymorphism with height and with bone mineral density (BMD) measured at the lumbar spine and femoral neck in 677 Caucasian women who were 18 to 35 years of age. Analysis of variance showed that individuals with 1 or 2 (AAAG)6 alleles were significantly taller than the others, and the significance remained after adjusting for multiple covariates. Comparison of genotype groups for BMD was not significant at the lumbar spine, but BMD was significantly higher at the femoral neck in the group with at least 1 (AAAG)6 allele. Scillitani et al. (2006) concluded that in vivo variation in promoter activity of the PTHR1 gene may be a relevant genetic influence on final adult height and BMD.
Lanske et al. (1996) investigated the functions of the PTH/PTHRP receptor by deletion of the murine gene by homologous recombination. Most PTH/PTHRP receptor -/- mutant mice died in midgestation, a phenotype not observed in PTHRP -/- mice, perhaps because of the effects of maternal PTHRP. Mice that survived exhibited accelerated differentiation of chondrocytes in bone, and their bones, grown in explant culture, were resistant to the effects of PTHRP and Sonic hedgehog (600725). These results suggested to Lanske et al. (1996) that the PTH/PTHRP receptor mediates the effects of Indian hedgehog and PTHRP on chondrocyte differentiation.
Chen et al. (2001) engineered a transgenic mouse with a ser365-to-cys substitution in Fgfr3 (134934), which is equivalent to a human mutation causing thanatophoric dysplasia type I (ser371 to cys; 134934.0006). The mutant mice exhibited shortened limbs as a result of markedly reduced proliferation and impaired differentiation of growth plate chondrocytes. The receptor-activating mutation also resulted in downregulation of expression of the Indian hedgehog (Ihh; 600726) and PTHRP receptor genes. Interactions between Fgfr3- and PTHRP-receptor-mediated signals during endochondral ossification were examined in cultured embryonic metatarsal bones. Consistent with the in vivo observations, Fgf2 (134920) inhibited bone growth in culture and induced downregulation of Ihh and PTHRP receptor gene expression. Furthermore, PTHRP partially reversed the inhibition of long bone growth caused by activation of Fgfr3; however, it impaired the differentiation of chondrocytes in an Fgfr3-independent manner. The authors hypothesized that Fgfr3 and Ihh-PTHRP signals may be transmitted by 2 interacting parallel pathways that mediate both overlapping and distinct functions during endochondral ossification.
Schipani et al. (1995), Fukumoto et al. (1996), Bettoun et al. (1997), and Minagawa et al. (2001) found no disease-causing mutations in the PTHR gene in patients with pseudohypoparathyroidism (PHP) type Ib (603233).
Hopyan et al. (2002) identified a mutant PTHR1 receptor in 2 of 6 patients with Ollier disease. The patients were heterozygous for a C-to-T transition resulting in an arg150-to-cys (R150C) substitution in the extracellular domain of PTHR1 in enchondroma specimens. In 1 of these men, the variant PTHR1 allele was carried in the germline and was inherited from the father. The mutated allele of the other affected male was thought to represent a somatic change, as normal bone adjacent to the enchondroma specimen did not contain the variant allele. It was possible that he was a mosaic carrier of the R150C allele, but this could not be tested because enchondroma tissue from only one site was available to study.
Rozeman et al. (2004) concluded that enchondromatosis is not caused by the PTHR1 R150C mutation found by Hopyan et al. (2002). This mutation was thought to result in upregulation of the Indian hedgehog (IHH)/parathyroid-related peptide (PTHrP) pathway. This was in contrast to previous studies that showed downregulation of this pathway in other cartilaginous tumors. Therefore, Rozeman et al. (2004) investigated PTHR1 in enchondromas and chondrosarcomas from 31 enchondromatosis patients (Ollier disease or Maffucci syndrome, lacking platyspondyly) from 3 different European countries, thereby excluding a population bias. PTHR1 protein expression was studied using immunohistochemistry, revealing normal expression. The presence of the R150C mutation was analyzed, using allele-specific oligonucleotide hybridization confirmed by sequence analysis, in tumors from 26 patients. In addition, 11 patients were screened for other mutations in the PTHR1 gene by sequence analysis. By both methods, Rozeman et al. (2004) could neither confirm the R150C mutation nor find any other mutations in the PTHR1 gene. Rozeman et al. (2004) stated that one explanation for the discrepancy in findings could be that the R150C mutation is specific for the Canadian population, i.e., a founder mutation. They also noted the possibility that the patients described by Hopyan et al. (2002) may belong to a rare subclass of enchondromatosis instead of having Ollier disease; in that case the R150C mutation may be specific for that rare variant.
In a patient with Jansen metaphyseal chondrodysplasia (MCDJ; 156400), Schipani et al. (1995) found heterozygosity for an A-to-G transition in exon M2 of the PTHR gene resulting in a change of the strictly conserved histidine residue at position 223 to arginine in the first intracellular loop of the receptor protein. Constitutive, ligand-independent adenosine 3-prime, 5-prime-monophosphate accumulation was observed in COS-7 cells expressing the mutant receptor but not in cells expressing the wildtype receptor. The finding explained the severe ligand-independent hypercalcemia and hypophosphatemia, and presumably the abnormal formation of endochondral bone in this disorder. The same mutation was found in a second patient (Juppner, 1995) but in the DNA from 2 others, no mutation was identified in PTHR. The 2 latter patients had either normal or only slightly elevated calcium levels. Since the disorder in all 4 cases was thought to be inherited in an autosomal dominant fashion and since the growth-plate findings were indistinguishable in both groups of patients, it appeared possible that the local overproduction of PTHR caused the bone abnormalities without causing hypercalcemia.
Schipani et al. (1999) analyzed genomic DNA from 4 additional sporadic cases with Jansen metaphyseal chondrodysplasia to search for novel activating mutations in PTHR1 to determine the frequency of 2 previously identified missense mutations, H223R and T410P (168468.0002), and to determine whether different mutations present with different severity of the disease. The H223R mutation was identified in 3 novel patients and was recognized as the most frequent cause of Jansen metaphyseal chondrodysplasia to that time.
To investigate further the activating mutations of the PTHR gene in Jansen metaphyseal chondrodysplasia (MCDJ; 156400), Schipani et al. (1996) analyzed genomic DNA from 6 additional patients. The H223R mutation (168468.0001) was found in 3 of the 6 patients but not in DNA from their healthy relatives or 45 unrelated normal subjects. A novel missense mutation that changed a threonine in the receptor's sixth membrane-spanning region to proline (T410P) was identified in another patient but not in 62 normal subjects. In 2 patients with radiologic evidence of this disorder but less severe hypercalcemia, no receptor mutations were detected. In COS-7 cells expressing PTH receptors with the T410P or H223R mutation, basal cyclic AMP accumulation was 4 to 6 times higher than in cells expressing wildtype receptors.
In a stillborn fetus with Blomstrand chondrodysplasia (215045), Jobert et al. (1998) found absence of functional receptors for parathyroid hormone and parathyroid hormone-related peptide caused by compound heterozygosity for mutations in the PTHR1 gene. From the mother the fetus had inherited a G-to-A transition at nucleotide 1176 in the exon that encodes the fifth transmembrane domain of the receptor. The mutation was predicted to result in an arg383-to-gln amino acid substitution in the receptor. Alternatively, this substitution created a novel splice acceptor site 33 nucleotides downstream from the normal splice acceptor site for exon M5. If this splice site were used, it would result in a mutant receptor in which the first 11 amino acids coded by exon M5 are deleted. Analysis of PTHR1 cDNA demonstrated that this heterozygous mutation indeed resulted in deletion of 11 amino acids, resulting from the use of the novel splice site created by the base substitution; the mutant receptor was well expressed in COS-7 cells, but did not bind PTH or PTH-related peptide, and failed to induce detectable stimulation of either cAMP or inositol phosphate production in response to these ligands; and the paternal allele was not expressed. Mice heterozygous for the knockout of the PTHR gene are phenotypically normal. Thus, the null mutation in the allele inherited from the father was significant. The patient in whom this mutation was demonstrated had been reported by Loshkajian et al. (1997).
Zhang et al. (1998) reported a patient with Blomstrand chondrodysplasia (215045) who was homozygous for a pro132-to-leu (P132L) mutation in the N-terminal portion of PTHR1. PTH-induced cAMP accumulation was severely reduced in COS-7 cells expressing P132L receptors when compared to that of cells expressing wildtype receptors, and PTH-induced inositol phosphate accumulation was not detected in cells expressing the mutant receptor. The authors concluded that because the amino acid mutated in the patient is otherwise conserved in all mammalian class II G protein-coupled receptors (see 600239), this abnormality may provide insights into structural features necessary for the normal functioning of this family of receptors.
In a patient with Blomstrand chondrodysplasia (215045), Karperien et al. (1999) identified homozygosity for an inactivating mutation in the PTHR1 gene, a deletion of a G at nucleotide 1122 in exon EL2. The mutation was inherited from both parents and was predicted to cause a shift, resulting in a truncated protein that completely diverged from the wildtype sequence after amino acid 364. The mutant receptor lacked transmembrane domains 5, 6, and 7, the connecting intra- and extracellular loops, and the cytoplasmic tail. Functional analysis of the mutant receptor in COS-7 cells and of dermal fibroblasts obtained from the patient proved that the mutation was inactivating.
Schipani et al. (1999) analyzed genomic DNA from 4 sporadic cases of Jansen metaphyseal chondrodysplasia (MCDJ; 156400) to search for novel activating mutations in PTHR1 to determine the frequency of the H223R (168468.0001) and T410P (168468.0002) mutations and to determine whether different mutations present with different severity of the disease. In 1 patient, a novel heterozygous missense mutation was found that changed isoleucine-458 in the receptor's seventh membrane-spanning region to arginine (I458R). In COS-7 cells expressing human PTHR1 with the I458R mutation, basal cAMP accumulation was approximately 8 times higher than that in cells expressing the wildtype receptor despite impaired surface expression of the mutant receptor. Furthermore, the I458R mutant showed higher responsiveness to PTH than the wildtype receptor in its ability to activate both the downstream effectors adenylyl cyclase and phospholipase C. Like the H223R and the T410P mutants, the I458R mutant had no detectable effect on basal inositol phosphate accumulation. Overall, the patient with the I458R mutation exhibited clinical and biochemical abnormalities similar to those in patients with the previously identified H223R and T410P mutations.
In a man and his 2 sons who were affected by a less severe form of Jansen metaphyseal chondrodysplasia (MCDJ; 156400), Bastepe et al. (2004) identified a heterozygous PTHR1 missense mutation, thr410 to arg (T410R). The 3 affected members of the family showed only mild skeletal dysplasia, comparatively normal stature, and blood calcium concentrations either within or at the upper end of the normal range. However, PTH levels were suppressed and urinary calcium excretion was elevated, which led to nephrolithiasis in both children. When expressed in COS-7 cells, T410R-mutant PTHR1 led to agonist-independent cAMP formation, which was less pronounced than that observed with the T410P (168468.0002) mutant.
In a consanguineous Turkish family with Eiken syndrome (EKNS; 600002), Duchatelet et al. (2005) found that affected individuals were homozygous for a 1656C-T transition in the last exon of the PTHR1 gene, resulting in a truncation mutation, arg485 to ter (R485X), in the C-terminal cytoplasmic tail of the protein.
In the first reported case of Blomstrand chondrodysplasia (215045) described by Blomstrand et al. (1985), Hoogendam et al. (2007) identified homozygosity for a 338C-T transition in the PTHR1 gene, causing a premature stop codon at position 104 (arg104-to-ter; R104X). The mutant protein consisted of only the signal peptide and the first 709 amino acids; it lacked all functional domains and was therefore completely inactivating.
In a male fetus with Blomstrand chondrodysplasia (215045), Hoogendam et al. (2007) identified homozygosity for a C-T transition at position +27 in intron M4 of the PTHR1 gene, creating a novel splice site. In dermal fibroblasts of this patient, the novel splice site was preferentially used, resulting in an aberrant transcript. The wildtype transcript was present, but at low levels.
In affected members of 2 German families with primary failure of tooth eruption (PFE; 125350), Decker et al. (2008) identified heterozygosity for a -3C-G splice site transversion in intron 11 (1050-3C-G) of the PTHR1 gene. Functional studies using gingival tissue from an affected individual showed that the mutant allele results in complete exclusion of exon 12, predicted to cause a frameshift at codon 351 and inclusion of 133 PTHR1-unrelated C-terminal amino acids. In vitro minigene reporter assay confirmed the skipping of exon 12. The mutation was not found in unaffected family members or in 178 German controls. Haplotyping at the PTHR1 locus revealed that the mutation originated from a common founder in the 2 families, with all affected individuals sharing an extended haplotype.
In a mother and 2 sons from a German family with primary failure of tooth eruption (PFE; 125350), Decker et al. (2008) identified heterozygosity for a +1G-A splice site transition in intron 8 (543+1G-A) of the PTHR1 gene. Minigene reporter assay analysis demonstrated loss of the donor splice site, predicting a frameshift and premature termination of the protein. The mutation was not found in the unaffected father and brother, or in 178 German controls.
In a father and son from a German family with primary failure of tooth eruption (PFE; 125350), Decker et al. (2008) identified heterozygosity for a 463G-T transversion in the PTHR1 gene, predicted to result in a glu155-to-ter (E155X) substitution. The mutation was not found in an unaffected daughter or in 178 German controls.
In a 7-year-old boy, born to first-cousin parents, with Eiken syndrome (EKNS; 600002), Moirangthem et al. (2018) identified homozygosity for a c.103G-A transition (c.103G-A, NM_000316.2) in exon 4 of the PTHR1 gene, resulting in a glu35-to-lys (E35K) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was present in heterozygous state in his unaffected parents. It was not found in the ExAC, gnomAD, or 1000 Genomes Project databases or in an in-house exome database of 417 families. Protein modeling predicted that the mutation would disrupt normal protein function.
In a 6-year-old Indian boy with Eiken syndrome (EKNS; 600002), Jacob et al. (2019) identified homozygosity for a c.401A-C transversion (c.401A-C, NM_000316.3) in the PTH1R gene, resulting in a tyr134-to-ser (Y134S) substitution. The mutation segregated with disease in the family and was not found in an in-house exome database or in public variant databases.
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