CYS-618 ARG MUTATION IN THE RET PROTOONCOGENE ASSOCIATED WITH FAMILIAL MEDULLARY-THYROID CARCINOMA AND MATERNALLY TRANSMITTED HIRSCHSPRUNGS-DISEASE SUGGESTING A ROLE FOR IMPRINTING

The multiple endocrine neoplasia type 2 (MEN2) syndromes and Hirschspr ung's disease (HSCR) are inherited neurocristopathies characterized by medullary thyroid carcinoma (MTC), pheochromocytoma, parathyroid dise ase, and gastrointestinal neuromatosis. Mutations in the RET proto-onc ogene are the underlying cause of the MEN2 syndromes and some cases of HSCR. In this report, we show that Cys 618 Arg mutation cosegregates with familial MTC and HSCR in two Moroccan Jewish families in which no involvement of pheochromocytoma or parathyroidism was observed. A sin gle haplotype shared by chromosomes bearing the Cys 618 Arg mutation i n both families strongly suggests a founder effect for this mutation. We have observed in our and in several other previously reported famil ies, an excess of maternal over paternal mutated RET alleles in offspr ings affected by HSCR. We suggest that parental imprinting may play a role in the ethiology of HSCR caused by mutations in the RET protoonco gene. (C) 1997 Wiley-Liss, Inc.