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Three cases of congenital central hypoventilation syndrome (CCHS) associated with Hirschsprung's disease (HSCR) were examined with respect to their genomic DNA on the coding region of the receptor tyrosine kinase (RET) and the endothelin-B receptor (EDNRB). No causative mutations for the disease were detected, but one polymorphism was observed in exon 11 of the RET proto-oncogene. In cases with CCHS, HSCR occurs with a high incidence, and this disease complex has been described as neurocristopathy due to aberrations in neural crest cell proliferation, differentiation or migration during the early fetal period. Both the RET and EDNRB may play important roles in the modulation of neurocristopathies; however, further systemic studies in a large population of patients and control subjects are necessary for elucidating the pathogenesis of this disorder.

Unlabelled: We report on mutation analysis of five genes involved in the receptor tyrosine kinase (RET) or the endothelin-signalling pathways in 28 sporadic Japanese patients with Hirschsprung disease. Analysis of DNA obtained from peripheral blood cells revealed six mutations in the RET proto-oncogene, four of which were disease-causing mutations in exon 9 (D584G), the splice donor site of intron 10 (+2T to A), exon 11 (A654T), and exon 12 (T706A). A heterozygous A to G transition was found in 47 bases upstream from the 5' end of exon 2 in two HD patients but was also seen in one control subject (2/28; 1/24). A silent 2307T to G transversion was observed in exon 13. Two disease-causing mutations were detected in the endothelin receptor (EDNRB) gene, in the non-coding region of exon 1 (-26 G to A) and in exon 4 (A301T); the latter mutation was a novel one. One silent mutation was observed in exon 4 (codon 277). One heterozygous T to C mutation was found in the glial cell line-derived neurotrophic factor gene in 25 bases upstream of the coding region in exon 1. No nucleotide changes were detected in either the endothelin-3 or neurturin genes. Disease-causing mutation rates in the RET proto-oncogene and the EDNRB gene were estimated at 14.3% (4/28) and 10.7% (3/28), respectively. In addition to mutations in the RET and EDNRB genes, embryonic environmental factors and/or other genetic factors appear to be involved in the development of Hirschsprung disease. Further systematic studies of genetic variation in a large series of patients and controls are necessary for elucidating the pathogenesis of this disorder., Conclusion: This study provides further gene alterations as disease-causing mutations in Japanese cases of sporadic Hirschsprung disease. However, the low mutation rate of the susceptibility genes may indicate that Hirschsprung disease arises from a combination of genetic and environmental factors.

A short-segment Hirschsprung disease (HSCR) patient associated with 21 trisomy showing point nucleotidic changes in both the receptor tyrosine kinase (RET) proto-oncogene and the endothelin-B receptor (EDNRB) gene is reported. A T to A heterozygous transition at the splicing donor site of the intron 10 in the RET proto-oncogene, and a G to A heterozygous substitution in non-coding region in the exon 1 of the EDNRB gene were observed. The familial analysis with these genes revealed that the origin of the former mutation was de novo and the latter one was maternal. No patient has been reported with two points mutations in different pathogenetically susceptible loci for HSCR. There is genetic evidence that the RET and EDNRB genes may interact in their susceptibility leading to HSCR.

A 5-year-old girl with congenital central hypoventilation syndrome associated with Hirschsprung's disease (Ondine-Hirschsprung syndrome) representing a missense mutation in exon 12 of the receptor tyrosine kinase (RET) proto-oncogene is reported. Using a direct sequencing technique, genomic DNA obtained from the patient's peripheral leukocytes was analyzed for its nucleotide sequences in all 20 exons of the RET proto-oncogene, seven regions of the 1st to the 7th exon of the endothelin-B receptor gene and endothelin 3 gene, including sequences corresponding to proteolytic cleavage sites. The analysis revealed that adenine at the 2116th base in the 12th exon in the RET proto-oncogene was substituted by guanine, supposedly resulting in a mutation of Thr 706 to Ala. No other mutational change was observed in the gene examined in this case. Mutation analysis has not been described previously on the gene in this disease complex. Mutation in this case might impair the maturation of the tyrosine kinase protein and subsequently cause neurocristopathy supposedly originating from the neural crest.