POSITIONAL CLONING OF MEN1 GENE

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Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with affected individuals developing parathyroid, gastrointestinal (GI) endocrine, and anterior pituitary tumors. The locus for MEN1 was linked to the PYGM marker at 11q13 9 years ago. Using a strategy involving physical mapping, meiotic mapping, LOH analysis, and candidate gene identification, we identified the gene responsible for MEN1 based on the germline mutations observed in nearly all probands tested. The process of identification of the gene by positional cloning approach required construction of a 2.8 Mb clone contig, generation of 20 new polymorphic markers and as many new transcripts from this interval. The MEN1 gene is expressed ubiquotously as a 2.8 kb transcript and encodes a protein, menin, of 67 kd with no homology to any known protein sequence. The mouse homologous gene was found to encode a protein 97% identical to human protein and is expressed ubiquotously and expression is observed as early as in a 7 day embryo. Menin appears to be located in the nucleus. A mouse model is being generated by homologous recombination.