HOMOZYGOSITY FOR A NULL ALLELE OF THE INSULIN-RECEPTOR GENE IN A PATIENT WITH LEPRECHAUNISM

Mutations in the insulin receptor gene can cause genetic syndromes ass ociated with extreme insulin resistance, We have investigated a patien t with leprechaunism (leprechaun/Qatar-1) born of a con sanguineous ma rriage. Postnatally, the proband had episodes of severe hypoglycemia a nd hyperinsu-linernia, with blood glucose levels ranging from 0.9 to 9 .9 mmol/L. The C peptide concentration with 1880 nmol/L, and the total insulin concentration was 1409 mU/L. The patient died outside the hos pital at the age of four months, All 22 exons of the patient's insulin reseptor gene were screened for mutations using denaturing gradient g el electrophoresis, Thereafter, the nucleotide sequences of selected e xons were determined directly. The patient was homozygous for a mutati on in exon 13; thirteen base pairs were deleted and replaced by a 5 b. p. sequence. This mutation shifts the reading frame and introduces a p remature chain termination codon downstream in exon 13. Thus, the muta nt allele is predicted to be a null allele that encodes a truncated re ceptor lacking both transmembrane and tyrosine kinase domains. (C) 199 5 Wiley Liss, Inc.