POINT MUTATION IN EXON-12 OF THE RECEPTOR TYROSINE KINASE PROTOONCOGENE RET IN ONDINE-HIRSCHSPRUNG-SYNDROME

A Ei-year-old girl with congenital central hypoventilation syndrome as sociated with Hirschsprung's disease (Ondine-Hirschsprung syndrome) re presenting a missense mutation in exon 12 of the receptor tyrosine kin ase (RET) proto-oncogene is reported. Using a direct sequencing techni que, genomic DNA obtained from the patient's peripheral leukocytes was analyzed for its nucleotide sequences in all 20 exons of the RET prot o-oncogene, seven regions of the 1st to the 7th exon of the endothelin -B receptor gene and endothelin 3 gene, including sequences correspond ing to proteolytic cleavage sites. The analysis revealed that adenine at the 2116th base in the 12th exon in the RET proto-oncogene was subs tituted by guanine, supposedly resulting in a mutation of Thr 706 to A la. No other mutational change was observed in the gene examined in th is case. Mutation analysis has not been described previously on the ge ne in this disease complex. Mutation in this case might impair the mat uration of the tyrosine kinase protein and subsequently cause neurocri stopathy supposedly originating from the neural crest.