Molecular Basis of Disease

The MEN1 gene maps to human chromosome 11q13 and was cloned in 1997.4 MEN1 is a tumor suppressor gene5 that contains 10 exons and encodes a ubiquitously expressed 2.8 kilobase (kb) transcript. The predicted 610 amino acid protein product, termed menin, exhibits no apparent similarities to any previously known proteins or consensus protein motifs, and its exact function is unknown. Menin is a nuclear protein that interacts with proteins involved in transcription and cell growth regulation. At least 400 different MEN1 mutations (nonsense, frameshift, insertion, deletion, missense, and splicing defects) have been described and are distributed throughout the 9.8 kb of genomic DNA comprising the MEN1 gene (Figure 20-1).3 At least 75% of all reported MEN1 mutations will produce a truncated menin protein primarily by nonsense and frameshift mutations. Missense and in-frame genomic alterations have been described in the domains of menin that interact with JUND, SMAD3, and NAKB1, three major effectors in transcription and cell growth regulation path-ways.6 These and other alterations that predict a loss of menin function are consistent with a role of MEN1 as a tumor suppressor gene.3 In mouse models of MEN1, loss of both MEN1 alleles in the mouse germline is lethal in the embryo but does not result in tumor formation.7 Conditional gene knockouts targeted to pancreatic islet P-cells or parathyroid cells result in growth of insulinomas or parathyroid adenomas, respectively.8,9 No correlation has been observed between MEN1 genotype and MEN1 phe-notype.1,3,10 In about 20% of MEN1 families no mutation in the MEN1 gene has been identified.11 Extensive listing and descriptions of MEN1 mutations are available online from the Human Gene Mutation Database Cardiff

177deIT 211ins15 299ins10 310insG 310dup5 - 316deI11 337deIC 359deI4 360dupGT 379deIAT-416delC 437insGG 441ins2 Q96X 485deIAT R98X 525deIC R108X R126X Y133X

711dupCA 738deI4 750deIG 757deI26

R183X E191X !

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