FUNCTIONAL-PROPERTIES OF A HETEROZYGOUS MUTATION (ARG(1174)-]GLN) IN THE TYROSINE KINASE DOMAIN OF THE INSULIN-RECEPTOR FROM A TYPE-A INSULIN-RESISTANT PATIENT

We analysed the biochemical properties of insulin receptors of a Type A insulin resistant patient with a single heterozygous point mutation substituting Gin for Arg(1174). Insulin binding capacity and affinty to Epstein-Barr virus transformed lymphocytes was normal. Quantitative analysis of autophosphorylation and substrate phosphorylation of soluble insulin receptors isolated from patient cells revealed no differences in the basal state whereas in the presence of insulin autophosphorylation activity was only 30% of control receptors. The stimulation of substrate phosphorylation and down-regulation of receptors on patient cells after chronic exposure to insulin was diminished when compared to controls. We conclude that the heterozygous Arg(1174) mutation does not perturb basal kinase activity but specifically interferes with the kinase activation by insulin and that the mutation has a dominant negative effect on the wild type kinase.