Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance.

Abstract

The nucleotide sequence-was determined for all 22 exons of the insulin receptor gene from three patients with genetic syndromes associated with extreme insulin resistance. In all three patients, insulin resistance was caused by decreased insulin binding to the cell surface. The patient with leprechaunism (leprechaun/Winnipeg) came from a consanguineous pedigree and was homozygous for a missense mutation substituting arginine for His2" in the a-subunit of the insulin receptor. The other two patients were both compound heterozygotes with a nonsense mutation in one allele of the insulin receptor gene, and a missense mutation in the other allele. In the patient with the Rabson-Mendenhall syndrome (patient RM-1), the missense mutation substituted lysine for Asn'5 in the a-subunit. In the patient with type A extreme insulin resistance (patient A-i), the missense mutation substituted serine for Asn462 in the a-subunit. Both nonsense mutations markedly reduced the levels of insulin receptor mRNA transcribed from the alleles with the nonsense mutation as compared to the transcripts from the other allele. The reduction in the level of mRNA would be predicted to greatly reduce the rate at which the truncated receptors would be synthesized. Furthermore, the truncated receptors would be severely impaired in their ability to mediate insulin action. (J. Clin. Invest. 1990. 86:254-264.)

Functional properties of a heterozygous mutation (Arg1174 → Gln) in the tyrosine kinase domain of the insulin receptor from a Type A insulin resistant patient

“…Indeed, many mutations of the insulin receptor gene have been identified over the past few years in patients with insulin resistance. Inherited defects of the insulin receptor gene may cause diminished receptor expression [1][2][3][4][5][6] or impaired receptor function, i.e. insulin binding [7,8] or tyrosine kinase activity [9][10][11].…”

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

“…The residual stimulatory effect of insulin on glucose uptake seen in patient's fibroblasts is probably mediated by hormone binding to the IGF-I receptor. A similar situation is seen with fibroblasts of leprechaun G [44] and Winn-1 [36]. The reason why a similar functional loss of insulin receptor can result in leprechaunism or Rabson-Mendenhall syndrome is unknown and additional factors may contribute to the pathogenesis of the full leprechaun phenotype.…”

“…The insulin receptor gene has been sequenced in two other patients with Rabson-Mendenhall syndrome. One patient [36] was also compound heterozygous. Similar to PK this patient RM-1 had a nonsense mutation at codon 1000 and a missense mutation in the amino-terminal extracellular receptor domain at codon 15.…”

“…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.…”

“…However, partially purified insulin receptors of PK were not autophosphorylated by incubation with IGF-I, indicating that IGF-I cannot activate the insulin receptor kinase in these cells. Several missense mutations have been characterized in the N-terminal c~-subunit of the insulin receptor which are all associated with incomplete processing and defective transport [36,[44][45][46][47][48] to the plasma membrane. Cor- Fig.6.…”