Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors of the parathyroids, pancreatic islets, and anterior pituitary. The MEN1 gene, on chromosome 11q13, has recently been cloned, and mutations have been identified. We have characterized such MEN1 mutations, assessed the reliability of SSCP analysis for the detection of these mutations, and estimated the age-related penetrance for MEN1. Sixty-three unrelated MEN1 kindreds (195 affected and 396 unaffected members) were investigated for mutations in the 2,790-bp coding region and splice sites, by SSCP and DNA sequence analysis. We identified 47 mutations (12 nonsense mutations, 21 deletions, 7 insertions, 1 donor splice-site mutation, and 6 missense mutations), that were scattered throughout the coding region, together with six polymorphisms that had heterozygosity frequencies of 2%-44%. More than 10% of the mutations arose de novo, and four mutation hot spots accounted for >25% of the mutations. SSCP was found to be a sensitive and specific mutational screening method that detected >85% of the mutations. Two hundred and one MEN1 mutant-gene carriers (155 affected and 46 unaffected) were identified, and these helped to define the age-related penetrance of MEN1 as 7%, 52%, 87%, 98%, 99%, and 100% at 10, 20, 30, 40, 50, and 60 years of age, respectively. These results provide the basis for a molecular-genetic screening approach that will supplement the clinical evaluation and genetic counseling of members of MEN1 families.

Here we report the first complete sequence and gene map of a human major histocompatibility complex (MHC), a region on chromosome 6 which is essential to the immune system. When it was discovered over 50 years ago the region was thought to specify histocompatibility genes, but their nature has been resolved only in the last two decades. Although many of the 224 identified gene loci (128 predicted to be expressed) are still of unknown function, we estimate that about 40% of the expressed genes have immune system function. Over 50% of the MHC has been sequenced twice, in different haplotypes, giving insight into the extraordinary polymorphism and evolution of this region. Several genes, particularly of the MHC class II and III regions, can be traced by sequence similarity and synteny to over 700 million years ago, clearly predating the emergence of the adaptive immune system some 400 million years ago. The sequence is expected to be invaluable for the identification of many common disease loci. In the past, the search for these loci has been hampered by the complexity of high gene density and linkage disequilibrium.

Our results provide further support for FIHP being a distinct allelic variant of MEN1, and an analysis of the 16 mutations reported to date indicate that FIHP is associated with a higher frequency of missense MEN1 mutations.

A Portuguese kindred with autosomal dominant isolated primary hyperparathyroidism (HPT) that was associated with parathyroid adenomas and carcinomas was investigated with the aim of determining the chromosomal location of this gene, designated HPT Port . Leukocyte DNA from 9 affected and 16 unaffected members and 7 parathyroid tumors from 4 patients was used in comparative genomic hybridization (CGH), tumor loss of heterozygosity (LOH), and family linkage studies. The CGH studies revealed abnormalities of chromosomes 1 and 13, and the results of LOH studies were consistent with the involvements of tumor suppressor genes from these regions. Family segregation studies mapped HPT Port to chromosome 1q22-q31 by establishing linkage with eight loci (D1S254, D1S222, D1S202, D1S238, D1S428, D1S2877, D1S422, and D1S412) (peak two-point LOD scores = 3.46-5.14 at 0% recombination), and defined the location of HPT Port to a 21 cM region flanked centromerically by D1S215 and telomerically by D1S306. Thus, HPT Port has been mapped to chromosome 1q22-q31, and a characterization of this gene will help to elucidate further the mechanisms that are involved in the development of parathyroid tumors. (J Bone Miner Res 1999;14:230-239)

The murine homolog of the multiple endocrine neoplasia type 1 (MEN1) gene (men1), which in humans is associated with tumors of the parathyroids, pancreas, and pituitary, has been characterized by isolating 27 clones from a mouse embryonic stem cell cDNA library. The insert sizes ranged from 600-2500 bp, and sequence analysis identified a 1833 bp open reading frame encoding a 611 amino acid protein. In addition, two clones contained an unspliced intron 1, and another two clones contained 20-29 bp of an upstream sequence, which suggested the presence of an alternate exon 1. This was supported by an analysis of the homologous human sequence. The mouse and human coding regions had 89% and 96% identity of the nucleotide and amino acid sequences, respectively. Investigation of clones isolated from a 129ola mouse genomic library, revealed the men1 gene to consist of 10 exons that spanned ∼6 kb. Northern blot analysis demonstrated the ubiquitous expression of 2.9 kb and 3.4 kb transcripts in mouse adult tissues and embryos from 7 days. DNA sequence analysis of the larger 3.4 kb transcript revealed it to result from a retention of intron 1. In situ hybridization confirmed an early ubiquitous expression in whole mount mouse embryos and adult tissues, but in the latter, different levels of cellular expression were observed, e.g., men1 expression was higher in testicular Sertoli cells than in germ cells. Thus, the mouse men1 gene and the basis of alternative transcripts have been defined, and these will help to facilitate studies of a mouse model. (J Bone Miner Res 1999;14:3-10)