MUTATIONS OF RET PROTOONCOGENE IN 3 KOREAN FAMILIES WITH MEN 2A - CLINICAL USE OF NEW RESTRICTION SITES FOR GENETIC DIAGNOSIS

Abnormalities in the ret proto-oncogene are found in several disorders such as multiple endocrine neoplasia (MEN) 2, sporadic medullary thyr oid cancer, congenital megacolon and papillary thyroid cancer. In MEN 2A or 2B, early genetic diagnosis before the development of clinical t umors is crucial for the cure of the disease. We studied mutations of ret proto-oncogene in 3 Korean families with MEN 2A and searched for n ew restriction sites that could be used for genetic diagnosis. By dire ct sequencing of exon 10 and 11 harboring 'hot' spots, heterozygous po int mutation was detected at positions translating cysteine codon in a ll 3 families. In 2 families, mutations at codon 634 in exon 11 were f ound (from TGC to CGC or TAG), yielding a new CfoI or RsaI restriction site. In one family, a mutation was located at codon 618 in exon 10 ( from TGC to CGC), generating a new CfoI restriction site. These new re striction sites were used in detecting 2 undiagnosed family members wi thout clinical symptoms or signs. In one of them, thyroidectomy was pe rformed to disclose a small medullary thyroid cancer. These results in dicate that Korean MEN 2A patients have germ-line mutations in the ret protooncogene at the cysteine residues like patients of other races, and the strategy employing direct sequencing to find mutations at 'hot spot' and search for ensuing new restriction sites could be a useful approach for the molecular diagnosis of genetic diseases accompanied b y mutations in restricted areas of disease genes such as MEN 2.