FREQUENCY OF RET MUTATIONS IN LONG-SEGMENT AND SHORT-SEGMENT HIRSCHSPRUNG DISEASE

Hirschsprung disease, or congenital aganglionic megacolon, is a geneti c disorder of neural crest development affecting 1:5,000 newborns, Mut ations in the RET proto oncogene, repeatedly identified in the heteroz ygous state in both long and short-segment Hirschsprung patients, lead to loss of both transforming and differentiating capacities of the ac tivated RET through a dominant negative effect when expressed in appro priate cellular systems, The approach of single strand conformational polymorphism analysis established for all the 20 exons of the RET prot o oncogene, and previously used to screen for point mutations in Hirsc hsprung patients allowed us to identify seven additional mutations amo ng 39 sporadic and familial cases of Hirschsprung disease (detection r ate 18%), This relatively low efficiency in detecting mutations of RET in Hirschsprung patients cannot be accounted by the hypothesis of gen etic heterogeneity, which is not supported by the results of linkage a nalysis in the pedigrees analyzed so far, Almost 74% of the point muta tions in our series, as well as in other patient series, were identifi ed among long segment patients, who represented only 25% of our patien t population, The finding of a C620R substitution in a patient affecte d with total colonic aganglionosis confirms the involvement of this mu tation in the pathogenesis of different phenotypes (i,e,, medullary th yroid carcinoma and Hirschsprung), Finally the R313Q mutation identifi ed for the first time in homozygosity in a child born of consanguineou s parents is associated with the most severe Hirsch sprung phenotype ( total colonic aganglionosis with small bowel involvement). (C) 1997 Wi ley-Liss, Inc.