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Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. The European Consortium on MEN1.

Claude Bernard University Lyon 1, Villeurbanne, Rhône-Alpes, France
Human Molecular Genetics (Impact Factor: 6.68). 08/1997; 6(7):1177-83. DOI: 10.1093/hmg/6.7.1177
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ABSTRACT Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterised by tumours of the parathyroids, pancreas and anterior pituitary that represents one of the familial cancer syndromes. The MEN1 locus has been previously localised to chromosome 11q13, and a <300 kb gene-rich region flanked centromerically by PYGM and telomerically by D11S1783 defined by combined meiotic and tumour deletion mapping studies. Two candidate genes, ZFM1 and PPP2R5B, from this region have been previously excluded, and in order to identify additional candidate genes we used a BAC to isolate cDNAs from a bovine parathyroid cDNA library by direct selection. One of the novel genes that we identified, SCG2, proved to be identical to the recently published MEN1 gene, which is likely to be a tumour suppressor gene. The SCG2 transcript was 2.9 kb in all tissues with an additional 4.2 kb transcript also being present in the pancreas and thymus. Mutational analysis of SCG2 in 10 unrelated MEN1 families identified one polymorphism and nine different heterozygous mutations (one missense, four non-sense, one insertional and three deletional frameshifts) that segregated with the disease, hence providing an independent confirmation for the identification of the MEN1 gene.

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    • "Menin functions as a tumor suppressor protein that is mutated in patients with an inherited syndrome called Multiple Endocrine Neoplasia 1 (MEN1) (Chandrasekharappa et al., 1997; Chandrasekharappa and Teh, 2001; Larsson et al., 1988). To date, more than 400 nonsense and frame-shift mutations have been reported in MEN1 patients often developing parathyroid, pancreatic or pituitary tumors after the loss of the wild-type MEN1 allele (Dong et al., 1997; Larsson et al., 1988; Lemmens et al., 1997; Thakker, 2001). Homozygous knockout of MEN1 (-/-) is embryonic lethal in mice, which die at the mid-gestation period with profound defects in liver, heart and the neural tube (Bertolino et al., 2003a; Crabtree et al., 2001; Stewart et al., 1998). "
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    • "Menin interacts with the N-terminus of MLL and is required for transformation by MLL fusion proteins (Caslini et al., 2007; Yokoyama et al., 2005). However, MEN1 mutations, which lead to loss of function of the Menin protein, are found in a variety of endocrine tumors including parathyroid hyperplasias and adenomas, as well as pancreatic islet tumor cells establishing Menin as a tumor suppressor (Chandrasekharappa et al., 1997; Lemmens et al., 1997). The similarities in the diseases associated with Menin and PAF subunit mutations (parathyroid and pancreatic islet tumors) raise the possibility that the mechanisms of oncogenicity may also be similar, perhaps mediated through cyclin dependent kinase deregulation as we have previously defined for Menin (Milne et al., 2005b). "
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    • ", were used as described previously [Pang et al., 1996; Bassett et al., 1998] to determine the haplotypes around the MEN1 locus, which is flanked by the PYGM and D11S1783 loci [Lemmens et al., 1997]. "
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