4 MUTANT ALLELES OF THE INSULIN-RECEPTOR GENE ASSOCIATED WITH GENETICSYNDROMES OF EXTREME INSULIN-RESISTANCE

We identified four novel mutant alleles of the insulin receptor gene i n three patients with genetic syndromes associated with insulin resist ance. Two mutant alleles of the insulin receptor gene were identified in a patient with the Rabson-Mendenhall syndrome who was a compound he terozygote for a mutation at the 3'-splice acceptor site of intron 4 ( AG-->GG;), the first mutation causing an aberrant splicing at this loc us, and a deletion of eight base pairs in exon 12. The second patient with leprechaunism was also a compound heterozygote for a deletion of one base pair in exon 19 and a mutation, Thr(910)-->Met, which causes impaired receptor processing. interestingly, the third patient with ty pe A syndrome was a simple heterozygote for the identical one base pai r deletion. The fact that the same one base pair deletion links to typ e A in a simple heterozygote and to leprechaunism in a compound hetero zygote appears consistent with the hypothesis that the severity of mut ations will determine the phenotype. (C) 1997 Academic Press.