A case of type A insulin resistance associated with heterozygous Asn462Ser mutation of the insulin receptor gene

Abstract

Mutations of the insulin receptor gene are responsible for monogenic forms of diabetes mellitus. Although the severity of the disease varies greatly with mutation type, mutations in both alleles of the gene tend to result in syndromes characterized by severe metabolic disorders whereas those in a single allele lead to less severe phenotypes. We report here a case of pronounced hyperinsulinemia, insulin resistance, and menstrual disorders associated with polycystic ovarian syndrome in a lean Japanese female. The patient manifested acanthosis nigricans and hirsutism during her childhood, and binding of insulin to her lymphocytes and erythrocytes during her infancy was low. She was found to be heterozygous for Asn462Ser mutation in the insulin receptor gene, consistent with diagnosis of type A insulin resistance. Although this mutation has previously been detected in association with additional mutations in the other allele of the insulin receptor gene in individuals with severe forms of insulin-resistance syndrome, a case of type A insulin resistance associated with this mutation alone has not been described. The Asn462Ser mutation has previously been shown not to affect binding of insulin to, or tyrosine autophosphorylation of, the insulin receptor, but it does impair dissociation of insulin from the receptor at low pH. These findings suggest that the Asn462Ser mutation of the insulin receptor alone can impair insulin action in the human body. Moreover, dissociation of insulin from the internalized insulin receptor on acidification of endosomes seems to be a required step in the biological function of the receptor.