Familial isolated hyperparathyroidism as a variant of multiple endocrine neoplasia type 1 in a large Danish pedigree

We report here our genetic findings of a family in which 14 members were af fected with isolated primary hyperparathyroidism. Hyperparathyroidism is th e main feature of multiple endocrine neoplasia type 1 (MEN1), making the re cently cloned MEN1 gene a prime candidate gene in this family. Significantl y positive lod scores were achieved with D11S4946 (3.36) and D11S4940 (3.53 ), and by combining the results from these two markers, a maximum positive lod score of 4.12 at recombination fraction 0.00 was obtained. Mutation ana lysis of MEN1 performed by full sequencing identified a missense mutation i n exon 4, causing an amino acid change from glutamine to proline at codon 2 60. This mutation (Q260P) was present in all affected family members, and t he inheritance of the mutation was in complete agreement with the disease-a ssociated haplotype. In comparison with the recent functional studies of th e menin protein interactions, this mutation is located in a region with lit tle or no binding activity to JunD and activating protein-1 transcription f actor. We conclude that some of the familial isolated primary hyperparathyr oidism families constitute a milder variant of MEN 1, which is associated w ith a functionally milder missense mutation.