A novel mutation of the MEN1 gene in a Japanese kindred with familial isolated primary hyperparathyroidism

Objective: To determine whether familial isolated hyperparathyroidism (FIHP ) is a variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed th e MEN1 gene in such a kindred. Design and methods: The study included the 70-year-old proband and nine rel atives, Blood was drawn for biochemical evaluation and germline mutation an alysis by direct sequencing of the MEN1 gene amplified by PCR, A hyperplast ic parathyroid gland obtained from a family member served for a loss of het erozygosity (LOH) study. Results: Three members from two generations in this kindred were found to h ave primary hyperparathyroidism, while none had clinical or biochemical evi dence of MEN1, MEN2 or hyperparathyroidism-jaw tumor syndrome. Analysis of germline DNA in the proband showed a missense mutation (GGC -> GAG) at codo n 305 in exon 7 of the MEN1 gene that predicts an amino acid change from gl ycine to aspartic acid (G305D). This mutation segregated with primary hyper parathyroidism in the kindred, and, in addition, there were two asymptomati c mutant-gene carriers at relatively advanced ages. In contrast, the mutati on was not detected in genomic DNA from five unaffected individuals and fro m 50 healthy subjects. The LOH study showed a loss of the wild-type allele, which confirmed that a functional defect of the MEN1 gene product, menin, is etiological for FIHP. Conclusions: FIHP is a genetically heterogeneous disease with a subset link ed to MEN1, most likely representing a variant of MEN1. The late onset and the reduced penetrance of disease found in this kindred may be related to t he site and the type of mutation, although the precise mechanism involved i s unknown at present.