Medical genetics: advances in brief

Abstract

Germ-line mutations oftheRET proto-oncogene inmultiple endocrine neoplasia type2A Mulligan LM,KwokJBJ,Healey CS,etal. Nature1993;363:458-60. MEN 2A isadominantly inherited cancer syndrome characterised bymedullary thyroidcarcinoma and phaeochromocytoma. Untilnow,family screening hasrelied on laborious biochemical investigation andit hasbeenunclear whetherthisshouldbe offered totherelatives ofisolated cases with single tumours. Mulligan etalhavenowused a'positional candidate' approach toidentify germline mutations intheRET oncogene on chromosome 10qll.2 in20outof23MEN 2Afamilies. RET waspreviously knownto showgross rearrangements in25%ofpapillary thyroid carcinomas, butinstriking contrast, themutations intheMEN 2Afamilies areallaminoacidsubstitutions, andin19 families thesamecysteine residue (codon 380)isinvolved. Fivedifferent mutations of thisresidue wereidentified andhaplotype analysis suggests thatsomeoftheindividual mutations mayhavemultiple independent origins. Ifconfirmed byother groups, these results wouldhaveimportant implications forscreening, asa highproportion of germline RET mutations couldbedetected withoutlaborious genome scanning methods. Asyetitisunclear whether MEN 2B (additionally associated withmucosal neuromatosis andMarfanoid habitus, and mapping tothesameregion of10q)isallelic, butIwouldbetthattheanswerwillnotbe longincoming.