MUTATION ANALYSIS OF THE MEN1 GENE IN MULTIPLE ENDOCRINE NEOPLASIA TYPE-1, FAMILIAL ACROMEGALY AND FAMILIAL ISOLATED HYPERPARATHYROIDISM

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant d isease characterized by neoplasia of the parathyroid glands, the endoc rine pancreas, and the anterior pituitary gland. In addition, families with isolated endocrine neoplasia, notably familial isolated hyperpar athyroidism (FIHP) and familial acromegaly, have also been reported. H owever, whether these families constitute MEN 1 variants or separate e ntities remains speculative as the genetic bases for these diseases ar e unclear. The gene for MEN 1 has recently been cloned and characteriz ed. Using single strand conformation analysis (SSCA) and sequencing, w e performed mutation analysis in: a) a total of 55 MEN 1 families from 7 countries, b) 13 isolated MEN 1 cases without family history of the disease, c) 8 acromegaly families, and d) 4 FIHP families. Mutations were identified in 27 MEN 1 families and 9 isolated cases. The 22 diff erent mutations spread across most of the 9 translated exons and inclu ded frameshift (11), nonsense (6), splice (2), missense mutations (2), and in-frame deletions (1). Among the 19 Finnish MEN 1 probands, a 14 66del12 mutation was identified in 6 families with identical 11q13 hap lotypes and in 2 isolated cases indicating a common founder. One frame shift mutation caused by 359del4 (GTCT) was found in 1 isolated case a nd 4 kindreds of different origin and haplotypes; this mutation theref ore represents a common ''warm'' spot in the MEN 1 gene. By analyzing the DNA of the parents of an isolated case one mutation was confirmed to be de novo. No mutation was found in any of the acromegaly and smal l FIHP families, suggesting that genetic defects other than the MEN 1 gene might be involved and that additional such families need to be an alyzed.