Brief Genetics Report Naturally Occurring Amino Acid Substitutions at Arg1174 in the Human Insulin Receptor Result in Differential Effects on Receptor Biosynthesis and Hybrid Formation, Leading to Discordant

Missense mutations in the tyrosine kinase domain of the human insulin receptor frequently result in a dominantly inherited form of insulin resistance. We noted a marked disparity in the clinical phenotypes of our study subjects with different missense mutations at the same residue (Arg1174) of the insulin receptor. Subjects with a tryp-tophan substitution (W) were only moderately hyperin-sulinemic, whereas those with a glutamine substitution (Q) had severe clinical and biochemical insulin resis-tance. Studies were undertaken to explore the molecular mechanisms underlying these differences. Both W and Q mutant receptors bound insulin normally but were kinase inactive. The W mutation resulted in more rapid degradation of newly synthesized mutant receptor, which contrasted with the near-normal biosynthesis o