HOMOZYGOSITY FOR A NEW MUTATION (ILE(119)-]MET) IN THE INSULIN-RECEPTOR GENE IN 5 SIBS WITH FAMILIAL INSULIN-RESISTANCE

Mutations in the insulin receptor gene can cause genetic syndromes suc h as leprechaunism that are associated with extreme insulin resistance . We have investigated a patient with leprechaunism born of a consangu ineous marriage. All 22 exons of the insulin receptor gene were screen ed for mutations using denaturing gradient gel electrophoresis. Therea fter, the nucleotide sequences of selected exons were determined direc tly. The patient was homozygous for a point mutation in exon 2 of the insulin receptor gene which results in the substitution of methionine for isoleucine at codon 119. Thus, the mutant allele encodes a recepto r that has a mutation in the putative insulin binding domain. Accordin gly, the mutant receptor would be predicted not to transduce the insul in signal effectively. In spite of a homozygous abnormality of the ins ulin receptor gene and many of the clinical features of severe insulin resistance, the proband's clinical syndrome was noticeably different from previously described patients with leprechaunism who usually die within the first six months of life. There are a total of nine childre n in the family, five of whom are homozygous for the Ile(119) --> Met mutation in the insulin receptor gene, and are clinically affected wit h varying degrees of severity. Four unaffected sibs are clinically nor mal; two are heterozygous carriers of the mutant allele, one is homozy gous for the normal allele, and one unaffected sib was not available f or molecular studies.