Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B)

Svensson, Pär-Johan; Anvret, Maria; Molander, Marie-Louise; Nordenskjöld, Agneta

doi:10.1007/s004390050797

Cited by 25 publications

(16 citation statements)

References 21 publications

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“…Interactions between RET and other loci, including EDNRB, may explain disease risk in subsets of HSCR families (25,28,(41)(42)(43)(44) ), the sex bias is extinguished, although we did not determine the influence of further reducing RET signaling in these mice. Although our interpretation must be tempered by differences in genetic backgrounds of the intercross strains, our data suggest that sex may be revealed or masked as a HSCR susceptibility factor, depending on the magnitude of effects at the mutant loci involved.…”

Section: Discussionmentioning

confidence: 92%

Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb

McCallion

Stames

Conlon

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

134

113

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Clinical expression of Hirschsprung disease (HSCR) requires the interaction of multiple susceptibility genes. Molecular genetic analyses have revealed that interactions between mutations in the genes encoding the RET receptor tyrosine kinase and the endothelin receptor type B (EDNRB) are central to the genesis of HSCR. We have established two locus noncomplementation assays in mice, using allelic series at Ednrb in the context of Ret kinase-null heterozygotes, to understand the clinical presentation, incomplete penetrance, variation in length of aganglionic segment, and sex bias observed in human HSCR patients. Titration of Ednrb in the presence of half the genetic dose of Ret determines the presentation of an enteric phenotype in these strains, revealing or abrogating a sex bias in disease expression depending on the genotype at Ednrb. RET and EDNRB signaling pathways are also critical for the normal development of other tissues, including the kidneys and neural crest-derived melanocytes. Our data demonstrate that interaction between these genes is restricted to the enteric nervous system and does not affect renal, coat color, and retinal choroid development. C omplex inheritance minimizes the impact of genetic variation and suppresses the potential expression of deleterious phenotypes by requiring the combined influence of mutant alleles at multiple loci to reveal a disease phenotype. Hirschsprung disease (HSCR) or aganglionic megacolon is a complex trait requiring the interaction of multiple genes for disease expression. Mutations in eight genes have already been identified in patients with HSCR and include RET, GDNF, NRTN, EDNRB, EDN3, ECE1, SOX10,. HSCR also displays several genetic hallmarks, including incomplete penetrance and pleiotropic effects of mutant genotypes, a marked sex difference in clinical expression, and variation in penetrance with extent of aganglionosis. Genetic and epigenetic modification of known mutations may provide a parsimonious explanation for these findings, suggesting that the majority of HSCR cases are likely to arise from the combined effects of multiple susceptibility genes. Although studies in mice have uncovered the disease phenotypes resulting from mutations within HSCR genes, we know little of the influence of variation in multiple genes or genetic background. Variants that abrogate a gene's capacity to moderate disease expression reveal interactions intrinsic to the associated trait. We have begun to dissect these interactions in enteric nervous system (ENS) development and HSCR and report specific genetic buffering interactions in ENS development and HSCR.HSCR is a congenital malformation with an incidence in the general population of 1͞5,000 live births (14, 15) and is characterized by an absence of neural crest (NC)-derived intrinsic ganglia along a variable length of the distal intestinal tract. The pathways mediated by the RET receptor tyrosine kinase and the G-protein-coupled endothelin receptor type B (EDNRB) are critical for the normal development of the ENS and ...

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Section: Discussionmentioning

confidence: 92%

Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb

McCallion

Stames

Conlon

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

134

113

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“…Similar to the receptor-ligand relationship between RET and GDNF observed in the etiology of some HD patients, in human fetuses, both EDNRB and EDN-3 have been demonstrated on enteric neurons and gut mesenchyme cells [31] , suggesting that EDN-3 and EDNRB may regulate interactions between neural crest and gut mesenchyme cells, necessary for normal migration. There are reports on HSCR patients with GDNF-RET or NTN-RET gene mutation combinations, as well as a case with mutations in both RET and EDNRB [32][33][34][35][36][37][38][39] . So far, there has been no report on an EDN-3 mutation in combination with a mutation in other HSCR genes.…”

Section: Discussionmentioning

confidence: 99%

Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung’s disease

Duan

Zhang²,

Li³

2003

WJG

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AIM:To investigate the mutation of EDNRB gene and EDN-3 gene in sporadic Hirschsprung's disease (HD) in Chinese population. METHODS:Genomic DNA was extracted from bowel tissues of 34 unrelated HD patients which were removed by surgery. Exon 3, 4, 6 of EDNRB gene and Exon 1, 2 of EDN-3 gene were amplified by polymerase chain reaction (PCR) and analyzed by single strand conformation polymorphism (SSCP). RESULTS:EDNRB mutations were detected in 2 of the 13 short-segment HD. One mutant was in the exon 3, the other was in the exon 6. EDN-3 mutation was detected in one of the 13 short-segment HD and in the exon 2. Both EDNRB and EDN-3 mutations were detected in one short-segment HD. No mutations were detected in the ordinary or longsegment HD.

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“…Whether E48D in EDN3 and N426N in EDNRB, contribute to the phenotype in combination with the mutations in RET is not known, but this certainly adds force to the interaction between pathways (18 -21 ). Mutations in GDNF and EDNRB have been found previously in the context of mutations in the RET locus (23,38,39 ). Even specific EDNRB mutations are known to require specific RET polymorphisms for transmission (20,28 ).…”

Section: Genotype-phenotype Correlationmentioning

confidence: 92%

“…R982C has been debated widely (36,37 ); it was initially described as a mutation but later was observed in control chromosomes (11,38 ). Interestingly, patient 55, who inherited R982C from her mother, also had two de novo silent mutations, T120T and G945G, both novel.…”

Section: Sequence Alterations In Ret and Gdnfmentioning

confidence: 99%

Highly Recurrent RET Mutations and Novel Mutations in Genes of the Receptor Tyrosine Kinase and Endothelin Receptor B Pathways in Chinese Patients with Sporadic Hirschsprung Disease

Garcia-Barceló

Sham²,

Lee

et al. 2004

Clinical Chemistry

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Background: Hirschsprung disease (HSCR) is a congenital disorder characterized by an absence of ganglion cells in the nerve plexuses of the lower digestive tract.HSCR has a complex pattern of inheritance and is sometimes associated with mutations in genes of the receptor tyrosine kinase (RET) and endothelin receptor B (EDNRB) signaling pathways, which are crucial for development of the enteric nervous system. Methods: Using PCR amplification and direct sequencing, we screened for mutations and polymorphisms in the coding regions and intron/exon boundaries of the RET, GDNF, EDNRB, and EDN3 genes of 84 HSCR patients and 96 ethnically matched controls. Results: We identified 10 novel and 2 previously described mutations in RET, and 4 and 2 novel mutations in EDNRB and in EDN3, respectively. Potential diseasecausing mutations were detected in 24% of the patients. The overall mutation rate was 41% in females and 19% in males (P ‫؍‬ 0.06). RET mutations occurred in 19% of the patients. R114H in RET was the most prevalent mutation, representing 7% of the patients or 37% of the patients with RET mutations. To date, such a high frequency of a single mutation has never been reported in unrelated HSCR patients. Mutations in EDNRB,

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Phenotypic variation in a family with mutations in two Hirschsprung-related genes (RET and endothelin receptor B)

Cited by 25 publications

References 21 publications

Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb

Phenotype variation in two-locus mouse models of Hirschsprung disease: Tissue-specific interaction between Ret and Ednrb

Clinical relationship between EDN-3 gene, EDNRB gene and Hirschsprung’s disease

Highly Recurrent RET Mutations and Novel Mutations in Genes of the Receptor Tyrosine Kinase and Endothelin Receptor B Pathways in Chinese Patients with Sporadic Hirschsprung Disease

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