Two Mutant Alleles of the Insulin Receptor Gene in a Patient with Extreme Insulin Resistance

Abstract

Insulin receptor complementary DNA has been cloned from an insulin-resistant patient with leprechaunism whose receptors exhibited multiple abnormalities in insulin binding. The patient is a compound heterozygote, having inherited two different mutant alleles of the insulin receptor gene. One allele contains a missense mutation encoding the substitution of glutamic acid for lysine at position 460 in the alpha subunit of the receptor. The second allele has a nonsense mutation causing premature chain termination after amino acid 671 in the alpha subunit, thereby deleting both the transmembrane and tyrosine kinase domains of the receptor. Interestingly, the father is heterozygous for this nonsense mutation and exhibits a moderate degree of insulin resistance. This raises the possibility that mutations in the insulin receptor gene may account for the insulin resistance in some patients with non-insulin-dependent diabetes mellitus.

Involvement of Heat Shock Protein 90 in the Degradation of Mutant Insulin Receptors by the Proteasome

“…Although there are some other mutants of the kinase domain that show the decreased insulin binding (43,44), it remains to be determined whether they are also degraded in the same manner as described above. On the other hand, in the ␣-subunit of the insulin receptor, only the Glu 460 mutation showed the accelerated receptor degradation (14). Since it was reported that the Glu 460 mutation caused lysosomal degradation of the insulin receptor on the way of recycling pathway, the mechanism of this degradation was different from that of Asp 1179 and Leu 1193 mutant receptors.…”

“…Among the various mechanisms for the insulin resistance in these patients, certain patients with the insulin receptor mutations showed a reduced number of insulin receptors on the cell surface although the mRNA of insulin receptor was normally expressed (1). Two major causes for this phenomenon have been described; the first is the impaired protein processing of mutated insulin receptors and accumulation in the endoplasmic reticulum (ER) 1 (3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13), and the second is the accelerated intracellular degradation of mutant receptor proteins (14,15). We previously reported the three families of type A insulin-resistant syndrome who had a mutation (Asp 1179 or Leu 1193 ) 2 in the kinase domain of the insulin receptor leading to the accelerated intracellular degradation of the unprocessed proreceptors (15).…”

W mutant mice with mild or severe developmental defects contain distinct point mutations in the kinase domain of the c-kit receptor.

“…Truncated forms of EGFR have been shown to act in a dominantnegative manner in in vitro cell lines [Basu et al 1989). Deletion of the kinase domain of the insulin receptor results in autosomal dominant inheritance of insulin resistance in humans (Kadowaki et al 1988;Taira et al 1989), and a point mutation in the ligand-binding domain of the human insulin receptor confers decreased insulin binding in cell culture and insulin resistance in heterozygote individuals {Klinkhamer et al 1989}.…”

An in-frame insertion in exon 3 and a nonsense mutation in exon 2 of the insulin receptor gene associated with severe insulin resistance in a patient with Rabson-Mendenhall syndrome

“…Multiple nonsense mutations have been described in the insulin receptor gene [34][35][36][37][38], most of which appeared to be associated with decreased levels of mRNA [35][36][37][38]. However, similar to the nonsense mutation at codon 672 in the paternal allele of leprechaun Ark-1 [34], direct cDNA sequencing of our patient showed that the allele with the nonsense mutation at codon Arg-86 is expressed almost to the same degree as the other insulin receptor allele.…”