PARENT-OF-ORIGIN EFFECTS IN MULTIPLE ENDOCRINE NEOPLASIA TYPE 2B

Multiple endocrine neoplasia type 2B (MEN 2B) is characterized by medu llary thyroid carcinoma, pheochromocytomas, mucosal neuromas, ganglion euromas, and skeletal and ophthalmic abnormalities. It is observed as both inherited and sporadic disease, with an estimated 50% of cases ar ising de novo. A single point mutation in the catalytic core region of the receptor tyrosine kinase, RET, has been observed in germ-line DNA of MEN 2B patients. We have analyzed 25 cases of de novo disease in o rder to determine the parental origin of the mutated RET allele. In al l cases the new mutation was of paternal origin. We observe a distorti on of the sex ratio in both de novo MEN 2B patients and the affected o ffspring of MEN 2B transmitting males. These results suggest a differe ntial susceptibility of RET to mutation in paternally and maternally d erived DNA and a possible role for imprinting of RET during developmen t.