IN-FRAME EXON-2 DELETION IN INSULIN-RECEPTOR RNA IN A FAMILY WITH EXTREME INSULIN-RESISTANCE IN ASSOCIATION WITH DEFECTIVE INSULIN BINDING - A CASE-REPORT

The phenotype and allelic expression of the insulin receptor gene is p resented in a family with a patient with type A insulin resistance. Co mpared to controls, insulin receptor binding in transformed lymphocyte s was 100%, 33% and 13% in the father, mother and proband, respectivel y. Reduced insulin receptor binding co-segregated with altered insulin receptor mRNA expression; the mother and daughter expressed eight ins ulin receptor mRNA species, including a set of four normal sized and a set of four shorter mRNA transcripts. In the proband the levels of th e normal sized mRNA transcripts were suppressed relative to the shorte r transcripts. Reverse polymerase chain reaction (PCR) revealed that t he shorter transcripts contained an in-frame deletion of exon 2. Seque ncing of the entire insulin receptor coding region revealed a paternal ly inherited A to T substitution in nucleotide 3205, converting isoleu cine 996 to phenylalanine, which does not co-segregate with reduced bi nding. Therefore, we hypothesize that two findings are necessary for t he presentation of type A insulin resistance in this patient: an in-fr ame deletion of the insulin receptor exon 2 that codes for amino acids crucial for insulin binding; and an inhibition of expression of the p aternal insulin receptor allele.