Abstract
We identified a heaterozygous missense mutation which substituted aspartic acid (GAC) for alanine (GCC) at codon 1048 of the insulin receptor gene in a patient with insulin resistance who showed typical symptoms of the genetic syndrome of extreme insulin resistance and low normal insulin receptor binding. We constructed a mutant insulin receptor cDNA by site-directed mutagenesis and investigated the function of the mutant receptor expressed by COS7 cells. We found that autophosphorylation of the mutant insulin receptors was markedly reduced. Ala1048 is located in the kinase domain of the insulin receptor β-subunit and conserved in most of protein-tyrosine kinases. Therefore, this amino acid is likely to play an important role in kinase activity of the insulin receptor. These results suggested that Ala1048→Asp1048 mutation of the insulin receptor was responsible for insulin resistance in this patient.
