Multiple endocrine neoplasia type 1 (MEN1) gene mutations in a subset of patients with sporadic and familial primary hyperparathyroidism target the coding sequence but spare the promoter region

Germ line mutations of the multiple endocrine neoplasia type I (MEN1) tumou r suppressor gene cause MEN1, a rare familial tumour syndrome associated wi th parathyroid hyperplasia, adenoma and hyperparathyroidism (HP). Here we i nvestigated the role of the MEN1 gene in isolated sporadic and familial HP. Using RT-PCR single strand conformational polymorphism screening, somatic (but not germ line) mutations of the MEN1 coding sequence were identified i n 6 of 31 (19.3%) adenomas from patients with sporadic primary HP, but none in patients (n=16) with secondary HP due to chronic renal failure. MEN1 mu tations were accompanied by a loss of heterozygosity (LOH) for the MEN1 loc us on chromosome 11q13 in the adenomas as detected by microsatellite analys is. No DNA sequence divergence within the 5' region of the MEN1 gene, conta ining the putative MEN1 promoter, was detectable in HP adenomas. Clinical c haracteristics were not different in HP patients with or without MEN1 mutat ion. Heterozygous MEN1 gene polymorphisms were identified in 9.6% and 25% o f patients with primary and secondary HP respectively. In a large kindred w ith familial isolated familial HP, MEN1 germ line mutation 249 del4 and LOH was associated with the HP phenotype and a predisposition to non-endocrine malignancies. We suggest that the bi-allelic somatic loss of MEN1 wild-typ e gene expression is involved in the pathogenesis of a clinically yet undef ined subset of sporadic primary HP adenomas. MEN1 genotyping may further he lp define the familial hyperparathyroidism-MEN 1 disease complex, but it se ems dispensable in sporadic primary HP.