The search for the MEN1 gene. The European Consortium on MEN-1.
The search for the gene whose mutations predispose individuals to multiple endocrine neoplasia type 1 (MEN-1) started in 1988 when the MEN1 locus was assigned to 11q13, close to PYGM. It came to an end with the recent identification of a gene expressed ubiquitously which harbours inactivating mutations associated with MEN-1. During these nine years, the genetic linkage interval had been slowly reduced, and losses of heterozygosity (LOH) in MEN-1 tumours had given strong indications that MEN1 was a tumour suppressor gene. It is ironic that MEN1 was finally found to be located less than 100 kb telomeric to PYGM. From the beginning, this gene was the most tightly linked genetically to MEN-1. In addition, LOH had already shown (in 1990) that it was the most likely centromeric boundary of the MEN1 minimal region. We recently narrowed the critical region to 900 kb through meiotic mapping, and established a 1200-kb sequence-ready contig consisting of cosmids, bacterial artificial chromosomes (BACs) and P1-derived artificial chromosomes (PACs), including three gene clusters (19 genes and 3 expressed sequence tags). Taking LOH results into account, the gene was likely to be present in the 300-kb area telomeric to PYGM that we had covered with BACs. One of the novel genes that we have identified by cDNA selection in this region, SCG2 (Suppressor Candidate Gene 2), proved to be identical to the recently published MEN1 gene. Mutation analysis of SCG2 in 11 unrelated MEN-1 families identified one nucleotide sequence polymorphism and 10 different mutations that segregated with the disease.