The search for the gene whose mutations predispose individuals to mult
iple 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 tha
t MEN1 was a tumour suppressor gene. It is ironic that MEN1 was finall
y found to be located less than 100 Bb telomeric to PYGM, From the beg
inning, 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 establishe
d a 1200-kb sequence-ready contig consisting of cosmids, bacterial art
ificial chromosomes (BACs) and P1-derived artificial chromosomes (PACs
), including three gene clusters (19 genes and 3 expressed sequence ta
gs). Taking LOH results into account, the gene was likely to be presen
t 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 th
is region, SCG2 (Suppressor Candidate Gene 2), proved to be identical
to the recently published MEN1 gene. Mutation analysis of SCG2 in 11 u
nrelated MEN-1 families identified one nucleotide sequence polymorphis
m and 10 different mutations that segregated with the disease.