Alternative titles; symbols
HGNC Approved Gene Symbol: EDNRB
SNOMEDCT: 715952000;
Cytogenetic location: 13q22.3 Genomic coordinates (GRCh38): 13:77,895,481-77,975,527 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 13q22.3 | ?ABCD syndrome | 600501 | Autosomal recessive | 3 |
| {Hirschsprung disease, susceptibility to, 2} | 600155 | Autosomal dominant | 3 | |
| Waardenburg syndrome, type 4A | 277580 | Autosomal dominant; Autosomal recessive | 3 |
Endothelins belong to a family of potent vasoactive peptides consisting of 3 isopeptides, ET1 (EDN1; 131240), ET2 (EDN2; 131241), and ET3 (EDN3; 131242). A diverse set of pharmacologic activities with different potencies are exerted by endothelin family peptides, suggesting the existence of ET receptor subtypes. Takayanagi et al. (1991) described 2 distinct subclasses of ET receptors, namely, ET1-specific and ET-nonselective. Vane (1990) recommended that the ET1-specific type be called ETA and the nonselective type ETB. Nakamuta et al. (1991) isolated a cDNA encoding human ETB receptor from a cDNA library constructed from human liver. Hepatocytes have a considerable number of ET receptors linked to biologic actions such as glycogenolysis. The cDNA had an open reading frame encoding a protein of 442 amino acid residues with a relative mass of 49,643. The deduced amino acid sequence of the human ETB receptor was 88% and 64% identical to those of rat lung ETB receptor and bovine lung ET1-specific receptor, respectively. Ogawa et al. (1991) likewise isolated a nonisopeptide-selective human endothelin receptor from a human placenta cDNA library. The predicted protein had 442 amino acids with a transmembrane topology similar to that of other G protein-coupled receptors.
Elshourbagy et al. (1996) isolated a novel splice variant of the endothelin-B receptor which they termed ETB-SVR. The sequence of the ETB-SVR receptor is identical to ETRB except for the intracellular C-terminal domain. The ETB-SVR receptor is expressed as a 2.7-kb mRNA in the lung, placenta, kidney, and skeletal muscle.
Elshourbagy et al. (1996) transfected COS cells with ETB-SVR or ETRB and found that both receptors bind to ET1. However, while ETRB-transfected cells responded to ET1 with increases in inositol phosphate accumulation and intracellular acidification, ETB-SVR-transfected cells did not exhibit either of these responses to ET1. These data suggested to Elshourbagy et al. (1996) that ETB-SVR and ETRB are functionally distinct, and that the difference in the C-terminal amino acid sequences determines functional coupling.
To investigate the influence of pregnancy-specific hormonal environment on expression of ET1 and ET1 receptor (EDNRA; 131243), Bourgeois et al. (1997) investigated whether the muscular layer of stem villi vessels could be a site of the ET1 expression. The authors found that whereas both EDNRA and EDNRB are present in stem villi vessels, placental vascular smooth muscle cells exclusively express the EDNRA.
Maggi et al. (2000) demonstrated that in FNC-B4 cells, which are derived from a human fetal olfactory epithelium, both sex steroids and odorants regulate GnRH secretion. They found biologic activity of EDN1 in this GnRH-secreting neuronal cell. In situ hybridization and immunohistochemistry revealed gene and protein expression of EDN1 and its converting enzyme (ECE1; 600423) in both fetal olfactory mucosa and FNC-B4 cells. Experiments with radiolabeled EDN1 and EDN3 strongly indicated the presence of 2 classes of binding sites, corresponding to the ETA (16,500 sites/cell) and the ETB receptors (8,700 sites/cell). Functional studies using selective analogs indicated that these 2 classes of receptors subserve distinct functions in human GnRH-secreting cells. The ETA receptor subtype mediated an increase in intracellular calcium and GnRH secretion.
Endothelin-1 inhibits active Na-K transport by as much as 50% in the renal tubule and other tissues (Zeidel et al., 1989). Okafor and Delamere (2001) noted that the presence of low levels of ET1 in aqueous humor combined with the potential for release of ET1 from ciliary processes suggested that the crystalline lens could be exposed to ET1 in vivo. They studied the influence of ET1 on active Na-K transport in the porcine lens. Their results suggested that ET1 inhibited active lens Na-K transport by activating EDNRA and EDNRB. Activation of the ET receptors also caused an increase in cytoplasmic calcium concentration in cultured lens epithelial cells. Both responses to ET1 appear to have a tyrosine kinase step.
The 5-prime region of EDNRB is a complex CpG island giving rise to 4 individual transcripts initiating within the island. Pao et al. (2001) analyzed the relationship between methylation and EDNRB expression in human tissues. The CpG island was unmethylated in normal prostate and bladder tissue, whereas it was methylated in colonic epithelium; DNA from tumors derived from these tissues was frequently hypermethylated. Analysis of 11 individual CpG sites in the CpG island showed that specific sites with high methylation levels in several tumors and cancer cell lines were also methylated in normal tissues, suggesting that these sites might serve as foci for further de novo methylation. A low methylation level in a small region within the 5-prime region correlated with expression of the 5-prime-most transcript, whereas almost complete methylation 200 to 1000 bp downstream of the transcriptional start site did not block expression of this transcript. Treatment with 5-aza-2-prime-deoxycytidine induced transcriptional activation of all 4 EDNRB transcripts. The authors concluded that there is differential, tissue-dependent methylation at the EDNRB 5-prime region, and that hypermethylation immediately 3-prime to the transcriptional start site does not prevent initiation. They further proposed a spreading mechanism for de novo methylation, starting from particular methylation hotspots.
Endothelin-1 is synthesized by keratinocytes in normal skin and is locally released after cutaneous injury. It is able to trigger pain through its actions on endothelin-A receptors of local nociceptors, but coincidentally produces analgesia through endothelin-B receptors. Khodorova et al. (2003) mapped an endogenous analgesic circuit, in which endothelin-B receptor activation induces the release of beta-endorphin from keratinocytes and the activation of G protein-coupled inwardly rectifying potassium channels (GIRKs, also called Kir-3) linked to opioid receptors on nociceptors. These results indicated the existence of an intrinsic feedback mechanism to control peripheral pain in skin, and established keratinocytes as an endothelin-B receptor-operated opioid pool.
Using gene expression profiling, Iwashita et al. (2003) determined that genes associated with Hirschsprung disease were highly upregulated in rat gut neural crest stem cells relative to whole-fetus RNA. The genes with highest expression were GDNF (600837), SOX10 (602229), GFRA1 (601496), and EDNRB. The highest expression was seen in RET (164761), which was found to be necessary for neural crest stem cell migration in the gut. GDNF promoted the migration of neural crest stem cells in culture but did not affect their survival or proliferation. The observations made by Iwashita et al. (2003) were confirmed by quantitative RT-PCR, flow cytometry, and functional analysis.
Wang et al. (2006) assessed EDNRB expression in human glaucomatous optic nerves and the spatial relationship between EDNRB and astrocytes. The frequency of positive EDNRB immunoreactivity was significantly higher in human glaucomatous optic nerves as compared with age-matched controls (9/16 vs 1/10). EDNRB colocalized with astrocytic processes and was quantitatively higher in the glaucomatous eyes. Wang et al. (2006) concluded that increased EDNRB immunoreactivity in diseased optic nerves and its association with astrocytes suggested that the glia-endothelin system might be involved in the pathologic mechanisms of neuronal degeneration.
Using transcription profiling of microdissected tumor endothelial cells from human ovarian cancers, Buckanovich et al. (2008) found that overexpression of ETBR was associated with absence of tumor-infiltrating lymphocytes and short patient survival time. An ETBR inhibitor increased adhesion of T cells to human endothelium in vitro, and this effect was countered by ICAM1 (147840) blockade or treatment with nitric oxide donors. Mice treated with the ETBR inhibitor displayed increased Icam1-dependent T-cell homing to tumors. ETBR inhibitor treatment enabled a tumor response in otherwise ineffective immunotherapy without altering the systemic antitumor immune response. Buckanovich et al. (2008) proposed that mixed ETAR-ETBR blockade could simultaneously target tumor cells through ETAR and enhance antitumor immune mechanisms through vascular ETBR.
Arai et al. (1993) demonstrated that the human genome contains a single copy of the ETRB gene, which spans 24 kb and comprises 7 exons and 6 introns. Every intron occurs near the border of the putative transmembrane domain in the coding region.
Using human/rodent somatic hybrid cell lines, Arai et al. (1993) assigned the ETRB gene to human chromosome 13.
Crystal Structure
Shihoya et al. (2016), reported the crystal structures of human endothelin type B receptor in the ligand-free form and in complex with the endogenous agonist endothelin-1 (131240). The structures and mutation analysis revealed the mechanism for the isopeptide selectivity between endothelin-1 and -3. Transmembrane helices 1, 2, 6, and 7 move and envelop the entire endothelin peptide in a virtually irreversible manner. The agonist-induced conformational changes are propagated to the receptor core and the cytoplasmic G protein-coupling interface, and probably induce conformational flexibility in TM6. A comparison with the M2 muscarinic receptor (CHRM2; 118493) suggested a shared mechanism for signal transduction in class A G protein-coupled receptors.
Susceptibility to Hirschsprung Disease 2
Puffenberger et al. (1994) presented evidence that Hirschsprung disease (HSCR2; 600155), an apparently multigenic disorder, can result in some cases from mutation in the endothelin-B receptor gene. EDNRB was a candidate gene because it mapped to the same region of chromosome 13 as did HSCR2. A trp276-to-cys mutation (W276C; 131244.0001) was dosage sensitive in that homozygotes and heterozygotes had a 74% and a 21% risk, respectively, of developing HSCR. For all clinical forms of HSCR, there is a greater incidence of megacolon in males than in females and the same was true for the specific EDNRB mutation. However, among the Mennonites, at least 5 megacolon patients did not seem to carry the W276C EDNRB mutation present in most of the affected members, which suggested the existence of as yet undiscovered HSCR susceptibility genes.
Kusafuka et al. (1996) analyzed 7 exons for mutations in the EDNRB gene in 41 isolated patients with HSCR. Two novel mutations were detected (131244.0003 and 131244.0004). Both patients with the novel mutations were heterozygotes. No information was provided on the families of these 2 cases, but the presumption was that they represented new mutations. Amiel et al. (1996) reported 3 missense mutations in the EDNRB gene in heterozygous state in sporadic cases of HSCR. Chakravarti (1996) tabulated 12 mutations in the EDNRB gene identified in cases of Hirschsprung disease up to that time.
Among 31 isolated cases of Hirschsprung disease in non-inbred populations in Japan, Tanaka et al. (1998) identified 3 new mutations in the EDNRB gene: 2 transversions, A to T and C to A at nucleotides 311 (N104I) and 1170 (S390R), respectively, and a T-to-C transition at nucleotide 325 (C109R). In vitro functional expression studies in Chinese hamster ovary cells revealed that N104I receptors showed almost the same binding affinities and functional properties as the wildtype and might represent a polymorphism. On the other hand, although S390R did not change the binding affinities, it caused decreases in the ligand-induced increment of intracellular calcium and in the inhibition of adenylyl cyclase activity, showing the impairment of the intracellular signaling. C109R receptors were proved to be localized near the nuclei as an unusual 44-kD protein with an extremely low affinity to endothelin-1 and not to be translocated into the plasma membrane.
Chakravarti (1996) estimated that RET (164761) mutations account for approximately 50% of HSCR cases and EDNRB mutations account for approximately 5%. Short-segment HSCR occurs in about 25% of RET-caused cases and in more than 95% of EDNRB-related cases. Whereas homozygosity for the EDNRB gene can cause deafness and pigmentary anomalies in addition to HSCR (e.g., 131244.0002), the homozygous phenotype for RET has not been observed.
Carrasquillo et al. (2002) noted that although 8 genes with mutations that can be associated with Hirschsprung disease had been identified, mutations at individual loci are neither necessary nor sufficient to cause clinical disease. They conducted a genomewide association study in 43 Mennonite family trios (parents and affected child) using 2,083 microsatellites and SNPs and a new multipoint linkage disequilibrium method that searched for association arising from common ancestry. They identified susceptibility loci at 10q11, 13q22, and 16q23 (HSCR8; 608462); they showed that the gene at 13q22 is EDNRB and the gene at 10q11 is RET. Statistically significant joint transmission of RET and EDNRB alleles in affected individuals and noncomplementation of aganglionosis in mouse intercrosses between Ret-null and the Ednrb hypomorphic piebald allele were suggestive of epistasis between EDNRB and RET. The findings suggested that genetic interaction between mutations in RET and EDNRB is an underlying mechanism for this complex disorder.
Sanchez-Mejias et al. (2010) screened the EDN3 (131242) and EDNRB genes in 196 patients with Hirschsprung disease from Spain using high performance liquid chromatography. They found 25 sequence variants in the EDNRB gene; 17 of these were novel. Sanchez-Mejias et al. (2010) screened an additional exon in the 5-prime direction from exon 1 of EDNRB, never previously analyzed in the context of HSCR. Inclusion of this additional exon results in a transcript variant, termed EDNRB-delta-3, with 89 additional amino acids at the N-terminal region of the protein relative to conventional EDNRB. Sanchez-Mejias et al. (2010) detected 3 sequence variants at the 5-prime untranslated region of this additional exon. The most striking finding was the detection of a coding mutation, lys15-to-ter (131244.0009), in a sporadic Hirschsprung disease patient.
Waardenburg Syndrome Type 4A
Puffenberger et al. (1994) found that some Mennonites had HSCR associated with nonenteric phenotypes, including bicolored irides (6.3%), hypopigmentation (2.5%), sensorineural hearing loss (5.1%), and white forelock (7.6%), reminiscent of the Shah-Waardenburg syndrome (WS4A; 277580). Puffenberger et al. (1994) suggested that these nonenteric features represented pleiotropic effects of the W276C mutation. They pointed out that the mouse piebald mutation 's' demonstrates white coat spotting as the only phenotypic trait, whereas the piebald-lethal mouse 's(l)' has megacolon in addition to white coat color (Lane, 1966). Hosoda et al. (1994) found that targeted and natural ('piebald-lethal') mutations of the Ednrb mouse result in megacolon associated with spotted coat color.
ABCD Syndrome
In a child with ABCD syndrome (600501) reported by Gross et al. (1995), Verheij et al. (2002) identified a homozygous nonsense mutation in the EDNRB gene (131244.0008). Verheij et al. (2002) concluded that the ABCD syndrome is not a separate entity, but rather an expression of Shah-Waardenburg syndrome (WS4).
The autosomal recessive 'spotting lethal' (sl) mutation in the rat is characterized by absence of intramural ganglion cells in the entire colon and distal small bowel, thus resembling human Hirschsprung disease. Ceccherini et al. (1995) excluded linkage of sl with 2 candidate genes, RET protooncogene (RET; 164761) and endothelin-3; however, a highly significant lod score (Z = 47.05 at theta = 0.0) was found between EDNRB and the sl phenotype. The exon-intron structure of the rat gene was reconstructed and each exon of the sl rat was screened for mutations. A 301-bp interstitial deletion, encompassing the distal half of the first coding exon (exon 2) and the proximal part of the adjacent intron, was demonstrated. This deletion resulted in 2 transcriptional products, 270 and 238 bp shorter than wildtype cDNA. Gariepy et al. (1996) showed that the deletion perfectly cosegregates with the sl phenotype. The deletion leads to production of an aberrantly spliced EDNRB mRNA that lacks the coding sequence for the first and second putative transmembrane domains of the G protein-coupled receptor. Radioligand binding assays revealed undetectable levels of functional EDNRB in tissues from homozygous sl/sl rats. Thus, the authors concluded that EDNRB plays an essential role in the normal development of 2 neural crest-derived cell lineages, epidermal melanocytes and enteric neurons, in 3 mammalian species--humans, mice, and rats. They stated that rats lacking EDNRB may prove valuable in studies of adult physiology in health and diseases, if the sl rat can be rescued from the lethal megacolon phenotype.
Gariepy et al. (1998) demonstrated that during normal rat development the EDNRB mRNA expression pattern is consistent with expression by enteric nervous system (ENS) precursors throughout gut colonization. They used the human dopamine-beta-hydroxylase (DBH; 223360) promoter to direct transgenic expression of EDNRB to colonizing ENS precursors in the sl/sl rat. The DBH-EDNRB transgene compensated for deficient endogenous EDNRB in these rats and prevented the development of congenital intestinal aganglionosis. The transgene had no effect on coat color spotting, indicating the critical time for EDNRB expression in ENS development begins after separation of the melanocyte lineage from the ENS lineage and a common precursor. The transgene dosage affected both the incidence and severity of the congenital intestinal defect, suggesting dosage-dependent events downstream of EDNRB activation in ENS development.
Shin et al. (1997) attempted to identify the important domains for EDNRB function by studying 4 recessive juvenile lethal alleles in the mouse Ednrb gene created either by radiation or chemical mutagens. Molecular defects were identified in 3; in 1 mutation, which is associated with normal levels of Ednrb mRNA in adult brain, the mutation appeared to affect important regulatory elements that mediate the expression of the gene during development.
Lethal white foal syndrome (LWFS) is a congenital anomaly of horses resembling Hirschsprung disease characterized by a white coat color and aganglionosis of the bowel. To investigate the molecular basis of LWFS, Yang et al. (1998) demonstrated that a full-length cDNA for horse EDNRB contains a 1,329-bp open reading frame that encoded 443 amino acid residues. The predicted amino acid sequence was 89%, 91%, and 85% identical to human, bovine, and mouse/rat EDNRB sequences, respectively, but only 55% identical to the human, bovine, and rat EDNRA sequences. When homozygous, a dinucleotide mutation, TC-to-AG, which changed isoleucine to lysine in the predicted first transmembrane domain of the EDNRB protein, was found as the basis of LWFS; the heterozygous state resulted in the 'overo' phenotype. The dinucleotide mutation involved nucleotides 353 and 354. It had previously been known that LWFS is produced most often by mating horses with the overo color pattern. One mutant allele produces the coat color change but the presence of at least 1 normal allele appears to protect against the development of aganglionosis.
Metallinos et al. (1998) also showed that an ile118-to-lys missense mutation in EDNRB is responsible for lethal white foal syndrome. Breedings between particular spotted horses, generally described as frame overo, produce some foals that, in contrast to their parents, are all white or nearly all white and die shortly after birth of severe intestinal blockage. These foals have aganglionosis characterized by a lack of submucosal and myenteric ganglia from the distal small intestine to the large intestine, similar to human Hirschsprung disease. Metallinos et al. (1998) found that lethal white foal syndrome occurred in homozygotes; heterozygotes showed the frame overo pattern. Horses with tobiano markings included some carriers, indicating that tobiano is epistatic to frame overo. In addition, some horses identified as carriers had no recognized overo coat pattern phenotype, demonstrating the incomplete penetrance of the mutation. Santschi et al. (1998) likewise studied the ile118-to-lys change in the overo lethal white syndrome in foals born to American Paint Horse parents of the overo coat pattern lineage.
To determine when EDNRB signaling is required during embryogenesis, Shin et al. (1999) exploited the tetracycline-inducible system to generate strains of mice that expressed Ednrb at different stages of embryogenesis. Shin et al. (1999) determined that Ednrb is required during a restricted period of neural crest development between embryonic days 10 and 12.5. Shin et al. (1999) concluded that EDNRB is required for the migration of both melanoblasts and enteric neuroblasts.
The role of the endothelin-B receptor in vascular homeostasis is controversial because the receptor has both pressor and depressor effects in vivo. Spotting lethal rats carry a naturally occurring deletion in the endothelin-B receptor gene that completely abrogates functional receptor expression. Rats homozygous for this mutation die shortly after birth due to congenital distal intestinal aganglionosis. Genetic rescue of homozygous rats from this developmental defect using a dopamine hydroxylase-EDNRB transgene resulted in ETB-deficient adult rats Gariepy et al. (2000). On a sodium-deficient diet, the rats exhibited a normal arterial blood pressure, but on a high-sodium diet the homozygous sl rats became severely hypertensive. Normal pressure was restored in the salt-fed rats when the epithelial sodium channel was blocked with amiloride. Gariepy et al. (2000) concluded that the rescued sl/sl rats are a novel single-locus genetic model of severe salt-sensitive hypertension. The results suggested that these rats are hypertensive because they lack the normal tonic inhibition of the renal epithelial sodium channel.
Matsushima et al. (2002) described a novel mutant mouse with a mutation in the Ednrb gene and proposed the mouse as an animal model of Waardenburg syndrome 4 (WS4; 277580), or Waardenburg-Shah syndrome, which combines Hirschsprung disease with features of Waardenburg syndrome. These mutants had a mixed genetic background and extensive white spotting. They died between 2 and 7 weeks after birth owing to megacolon; their colon distal to the megacolon lacked Auerbach plexus cells. These mutants did not respond to sound, and the stria vascularis of their cochleae lacked intermediate cells, i.e., neural crest-derived melanocytes. The inheritance was autosomal recessive as in human WS4. Breeding analysis revealed that WS4 mice are allelic with piebald-lethal and JF1 mice, which are also mutated in the Ednrb gene. Mutation analysis showed that the Ednrb gene lacked 318 nucleotides encoding transmembrane domains owing to deletion of exons 2 and 3. Interaction between endothelin-3 (131242) and its receptor is required for normal differentiation and development of melanocytes and Auerbach plexus cells.
Carpenter et al. (2003) studied pulmonary edema formation in EDNRB-deficient rats. In normoxia, EDNRB -/- rats had significantly more lung vascular leak than heterozygotes or controls. Hypoxia increased vascular leak regardless of genotype, and hypoxic EDNRB-deficient rats leaked more than hypoxic controls. EDNRB-deficient rats had higher lung endothelin levels in both normoxia and hypoxia. Lung hypoxia-inducible factor-1-alpha (HIF1A; 603348) and vascular endothelial growth factor (VEGF; 192240) levels were greater in the EDNRB-deficient rats in both normoxia and hypoxia, and both levels were reduced by EDNRA antagonism. Both EDNRA blockade and VEGF antagonism reduced vascular leak in hypoxic EDNRB-deficient rats. Carpenter et al. (2003) concluded that EDNRB-deficient rats display an exaggerated lung vascular protein leak in normoxia, that hypoxia exacerbates that leak, and that this effect is in part attributable to an endothelin-mediated increase in lung VEGF content.
Migration of the precursors of the enteric nervous system (ENS) into the colon requires expression of the EDNRB gene at a defined time. In studies in mice, Zhu et al. (2004) found a conserved spatiotemporal ENS enhancer of Ednrb. This 1-kb enhancer was activated as the ENS precursors approached the colon, and partial deletion of the enhancer at the endogenous Ednrb locus resulted in pigmented mice that died postnatally from megacolon. In the Ednrb ENS enhancer, they identified binding sites for Sox10 (602229), an SRY-related transcription factor associated with Hirschsprung disease, and mutational analyses of these sites suggested that SOX10 may have multiple roles in regulating EDNRB in the ENS.
Cantrell et al. (2004) tested for association between genes in the endothelin signaling pathway and severity of aganglionosis in an extended pedigree of B6C3FeLe.Sox10(Dom) mice. Single-locus association analysis identified interaction between EdnrB and Sox10. Additional analysis of F2 intercross progeny confirmed a highly significant effect of EdnrB alleles on the Sox10(Dom/+) phenotype. The presence of C57BL/6J alleles at EdnrB was associated with increased penetrance and more severe aganglionosis in Sox10(Dom) mutants. Crosses between EdnrB and Sox10 mutants corroborated this gene interaction, with double-mutant progeny exhibiting significantly more severe aganglionosis. The background strain of the EdnrB mutant further influenced the phenotype of Sox10/EdnrB double-mutant progeny, implying the action of additional modifiers on this phenotype.
In adult transgenic mice with conditional cardiac-restricted ET1 overexpression, Yang et al. (2004) observed nuclear factor kappa-B (see 164011) translocation, cytokine expression, inflammation and hypertrophy, resulting in dilated cardiomyopathy, congestive heart failure, and death as early as 5 weeks after transgene induction. Significant prolongation of survival was observed with a combined EDNRA/EDNRB antagonist but not with an EDNRA-selective antagonist, consistent with an important role for EDNRB in this model.
In an extensive Mennonite kindred with many cases of Hirschsprung disease (600155), Puffenberger et al. (1994) found a G-to-T missense mutation in exon 4 of the EDNRB gene, resulting in substitution of the highly conserved tryptophan-276 residue with a cysteine residue (W276C) in the fifth transmembrane helix of the G protein-coupled receptor. The mutant W276C receptor exhibited a partial impairment of ligand-induced Ca(2+) transient levels in transfected cells. HSCR was observed in 74% of W276C homozygotes and 21% of W276C heterozygotes. In addition to HSCR, nonenteric manifestations suggestive of Waardenburg-Shah syndrome (WS4A; 277580) were observed in individuals with the mutation: bicolored irides in 6.3%, hypopigmentation in 2.5%, sensorineural hearing loss in 5.1%, and white forelock in 7.6%.
In 2 girls born to consanguineous Tunisian parents, Attie et al. (1995) described features of both Waardenburg syndrome and Hirschsprung disease (277580). They excluded RET and PAX3 (606597) as candidate genes by linkage analysis but found a homozygous missense mutation in exon 2 of the EDNRB gene. Using microsatellite DNA markers flanking the EDNRB gene, they showed that the 2 affected sibs were geno-identical and homozygous at these loci, whereas the 2 unaffected brothers shared no more than 1 allele with their affected sisters. The affected sisters showed an abnormal SSCP pattern in exon 2 and direct DNA sequencing revealed a C-to-G transversion at the second nucleotide of codon 183, predicted to result in the replacement of an alanine by a glycine (A183G) in the third transmembrane domain of EDNRB. The parents and 1 healthy brother who was studied were heterozygous for the A183G mutation. Neither affected sister had dystopia canthorum. However, both had deafness, white forelock, and heterochromia iridis, as well as Hirschsprung disease.
In an isolated case of Hirschsprung disease (600155), Kusafuka et al. (1996) identified a G-to-A transition at nucleotide 824 of the EDNRB gene. The patient was heterozygous and apparently this represented a new mutation. Aganglionosis was confined to the rectosigmoid colon and there was no associated abnormality. The mutation converted a TGG (trp) codon to a stop codon at residue 275.
In an isolated case of Hirschsprung disease (600155), Kusafuka et al. (1996) found insertion of a T after nucleotide 878 in the EDNRB gene. The patient was heterozygous and presumably represented a new mutation, although no family studies were performed. The mutation caused a frameshift with early termination of translation at nucleotide 894. The aganglionosis was confined to the descending colon, and there were no associated abnormalities.
Svensson et al. (1998) described a family with Hirschsprung disease (600155) with missense mutations in both the RET gene (arg982 to cys; 164761.0036) and the EDNRB gene, gly57 to ser (G57S). In this family, 3 of 5 members had both mutations, but only 1, a boy, had the Hirschsprung disease phenotype. Hofstra et al. (1997) found the G57S mutation in 3 of 40 HSCR patients, but also in 4 of 180 control chromosomes. With the controls studied by Svensson et al. (1998), the figure comes to 4 of 410 control chromosomes. In the family of Svensson et al. (1998) the mother and a daughter carried both mutations; the G57S mutation was present in homozygous state in the daughter who had inherited the mutation from each parent. The fact that family members are healthy carriers of G57S in hetero- or homozygous form suggested a sex-dependent gene-dosage effect, comparable to that observed by Puffenberger et al. (1994) in a Mennonite kindred with the trp276-to-cys mutation (131244.0001), in which there were heterozygous as well as homozygous healthy carriers of the founder mutation. The penetrance was higher in males, however.
In a patient with Hirschsprung disease (600155), Auricchio et al. (1999) found double heterozygosity for a silent mutation, I647I, of the RET gene (164761.0037), inherited from the unaffected mother, and an EDNRB missense mutation, S305N, transmitted by the healthy father. In 2 different patients they demonstrated both in vivo and in vitro that the silent RET mutation can interfere with correct transcription, possibly leading to a reduced level of the RET protein. The coexistence in the same patient of 2 functionally significant EDNRB and RET mutations suggested a direct genetic interaction between these 2 distinct transmembrane receptors in polygenic HSCR disease.
Lek et al. (2016) questioned the validity of this variant as a susceptibility allele because it has a high global allele frequency (0.0089) in the ExAC database.
In a family with Waardenburg-Shah syndrome (277580), Syrris et al. (1999) identified a heterozygous C-to-T transition in exon 3 of the EDNRB gene, resulting in an arg253-to-ter (R253X) substitution resulting in premature termination. The mutation was not observed in over 50 unrelated controls. The data confirmed the role of EDNRB in the cause of Waardenburg-Shah disease and demonstrated that in this disorder there is a lack of correlation between phenotype and genotype and a variable expression of disease even within the same family. The family studied by Syrris et al. (1999) was of Afro-Caribbean origin and had a history of sensorineural deafness, heterochromia iridis, and Hirschsprung disease. Synophrys, hair or skin hypopigmentation, and dystopia canthorum were absent in this family.
In the fifth child affected with ABCD syndrome (600501) in a consanguineous Kurdish family, previously described by Gross et al. (1995), Verheij et al. (2002) identified a homozygous C-to-T transition in the EDNRB gene, resulting in the substitution of a stop codon for an arginine residue in exon 3 (R201X). The affected female infant presented with bilateral deafness, albinism, a black lock at the right temporooccipital region, and spots of retinal depigmentation. She also had a severe defect of intestinal innervation from which she died at 5 weeks of age. Verheij et al. (2002) suggested that ABCD syndrome is not a separate entity, but an expression of Shah-Waardenburg syndrome (277580).
In a Spanish male patient with sporadic Hirschsprung disease (600155), Sanchez-Mejias et al. (2010) identified an A-to-T transversion at nucleotide 43 of the EDNRB gene, resulting in a lysine-to-termination substitution in codon 15 (K15X). This mutation was not identified in any other family members other than the father from whom the child inherited it. The father did not have Hirschsprung disease.
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