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 clinical phenotypes

Missense mutations in the tyrosine kinase domain of the human insulin recep tor frequently result in a dominantly inherited form of insulin resistance. We noted a marked disparity in the clinical phenotypes of our study subjec ts with different missense mutations at the same residue (Arg1174) of the i nsulin receptor. Subjects with a tryptophan substitution (W) were only mode rately hyperinsulinemic, whereas those with a glutamine substitution (Q) ha d severe clinical and biochemical insulin resistance. Studies were undertak en to explore the molecular mechanisms underlying these differences. Both W and Q mutant receptors bound insulin normally but were kinase inactive. Th e W mutation resulted in more rapid degradation of newly synthesized mutant receptor, which contrasted with the near-normal biosynthesis of the Q rece ptor. The propensity of the W receptor to form hybrids with the cotransfect ed wild-type (WT) receptor was also markedly impaired compared with the Q r eceptor, to an extent greater than could be explained by lower steady-state expression. Thus, the more clinically benign consequences of the heterozyg ous W mutant receptor are likely to relate to its impaired biosynthesis and /or reduced capacity to form hybrids with WT receptors, In addition to prov iding an explanation for the milder phenotype of 1174W versus 1174Q carrier s, these studies provide further support for the notion that the dominant-n egative effect of insulin receptor tyrosine kinase mutations involves the c ompetition between inactive mutant homodimers and WT/mutant hybrids with ac tive WT homodimers for both ligands and intracellular substrates.