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Familial multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with affected individuals developing parathyroid, gastrointestinal (GI) endocrine, and anterior pituitary tumors. Four large kindreds from the Burin peninsula/Fortune Bay area of Newfoundland with prominent features of prolactinomas, carcinoids, and parathyroid tumors (referred to as MEN1Burin) have been described, and they show linkage to 11q13, the same locus as that of MEN1. Haplotype analysis with 16 polymorphic markers now reveals that representative affected individuals from all four families share a common haplotype over a 2.5 Mb region. A nonsense mutation in the MEN1 gene has been found to be responsible for the disease in the affected members in all four of the MEN1Burin families, providing convincing evidence of a common founder. Hum Mutat 11:264–269, 1998. Published 1998 Wiley-Liss, Inc.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder that manifests as varying combinations of tumors of endocrine and other tissues (parathyroids, pancreatic islets, duodenal endocrine cells, the anterior pituitary and others). The MEN1 gene is on chromosome 11q13; it was recently identified by positional cloning. We previously reported 32 different germline mutations in 47 of the 50 familial MEN1 probands studied at the NIH. Eight different germline MEN1 mutations were encountered repeatedly in two or more apparently unrelated families. We analyzed the haplotypes of families with recurrent MEN1 mutations with seven polymorphic markers in the 11q13 region surrounding the MEN1 gene (from D11S1883 to D11S4908). Disease haplotypes were inferred from germline DNA and also from tumors with 11q13 loss of heterozygosity. Two different disease haplotype cores were shared by apparently unrelated families for two mutations in exon 2 (five families with 416delC and six families with 512delC). These two repeat mutations were associated with the two founder effects that we reported in a prior haplotype analysis. The disease haplotypes for each of the other six repeat mutations (seen twice each) were discordant, suggesting independent origins of these recurrent mutations. Most of the MEN1 germline mutations including all of those recurring independently occur in regions of CpG/CpNpG, short DNA repeats or single nucleotide repeat motifs. In conclusion, recurring germline mutations account for about half of the mutations in North American MEN1 families. They result from either founder effects or independent occurrence of one mutation more than one time. Hum Mutat 12:75–82, 1998. Published 1998 Wiley-Liss, Inc.1