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

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. Schematic representation of the chromosome 11q13 region containing the MEN1 gene. The locations of 19 genes [three of which, VRF, PLCB3 and PYGM, (7,10) are polymorphic], three ESTs (D11S2196E, IB408 and EST103356) and four polymorphic loci (D11S457, D11S427, D11S1783 and D11S449) which were previously established by physical mapping (7) and as part of a sequence ready contig (10) are shown. Family linkage studies (i.e. meiotic mapping) had mapped the MEN1 locus telomeric to VRF and centromeric to D11S1783 (10) and LOH studies of tumours (8,9) indicated a location of MEN1 telomeric to PYGM. The combined results of meiotic mapping and LOH studies indicated that the MEN1 gene was located in the <300 kb region flanked centromerically by PYGM and telomerically by D11S1783. Two candidate genes ZFM1 and PPP2R5B had been excluded as the MEN1 gene by mutational analysis (12,13). The BAC 180J2, which contained PYGM and the more telomeric locus ZFM1, was used to isolate additional cDNAs.