Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients

Abstract

Defects in insulin-receptor function have been associated with insulin-resistant states such as obesity and non-insulin-dependent diabetes mellitus (NIDDM). Several types of mutations in the insulin-receptor gene have been identified in patients with genetic syndromes of extreme insulin resistance. In some patients, insulin resistance results from a decrease in the number of insulin receptors on the cell surface. In one patient with leprechaunism (leprechaun/Minn-1), there is greater than 90% decrease in the levels of insulin-receptor mRNA. This patient is a compound heterozygote for two mutations in the insulin-receptor gene, both of which act in a cis-dominant fashion to decrease levels of mRNA transcribed from that allele. In one allele, there is a nonsense mutation at codon 897. All 22 exons of the other allele have a normal sequence, so that the mutation in this allele appears to map outside the coding sequence of the gene. Impaired insertion in the plasma membrane also causes insulin resistance. In two sisters (patients A-5 and A-8) with type A extreme insulin resistance, there is an 80-90% decrease in the number of insulin receptors expressed on the surface of their cells. Both sisters, whose parents are first cousins, are homozygous for a point mutation in which valine is substituted for phenylalanine at position 382 in the alpha-subunit of the insulin receptor. This mutation retards the posttranslational processing of the receptor and impairs the transport of receptors to the cell surface. Another patient with leprechaunism (leprechaun/Ark-1) is a compound heterozygote with two different mutant alleles of the insulin-receptor gene. In the allele derived from the father, there is a nonsense mutation at codon 672 that truncates the insulin receptor by deleting the COOH-terminal of the alpha-subunit and the entire beta-subunit. This truncated receptor, lacking a transmembrane domain, appears not to be expressed at the plasma membrane. In leprechaun/Ark-1, there is a missense mutation in the allele of the insulin-receptor gene derived from the mother. This point mutation results in substitution of glutamic acid for lysine at position 460 in the COOH-terminal half of the alpha-subunit. This mutation increases receptor affinity and impairs the ability of acid pH to dissociate insulin from the receptor within the endosome. There is a defect in recycling the receptor back to the plasma membrane associated with this defect. This results in an accelerated rate of receptor degradation and a consequent decrease in the number of receptors on the cell surface in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)

Directing traffic in neural cells: determinants of receptor tyrosine kinase localization and cellular responses

“…This difference in potency is likely because of TGFa-mediated recycling of the EGFR and sustained signal transduction. Consistent with this idea, a mutant insulin receptor (IR) that has increased binding to insulin in an acidic endosomal environment was identified in a patient with severe insulin resistant diabetes (Taylor et al 1990). …”

“…Consequently, the receptor mutant is degraded rather than recycled to the plasma membrane (Taylor et al 1990). Based on these experimental and clinical data, it is postulated that ligands may be modified to achieve desired changes in intracellular trafficking and thereby preferentially modify biological responses (French et al 1995).…”

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

“…Characterization of mutant insulin receptors in patients with severe forms of insulin resistance [5,[12][13][14][15][16][17] has helped not only to elucidate structure-function relationships of the receptor protein, but also to understand its role in the pathogenesis of diabetes. The patient we have studied has a severe form of insulin-resistant diabetes and decreased cellular insulin binding.…”

“…The a-subunit binds insulin and the intracellular domain of the/3-subunit is an insulinstimulated tyrosine-specific protein kinase [11]. Recently, several natural occurring mutations in the insulin receptor gene have been characterised in patients with insulin resistance and these characterisations have helped to elucidate the molecular mechanisms of insulin action [5,[12][13][14][15][16][17]. In this study we show a structural defect in the extracellular domain of the insulin receptor in an insulin-resistant patient with reduced cellular insulin binding due to two mutant alleles.…”

Clinical implications of hyperinsulinaemia in women

“…In many of the reports the cause of insulin resistance is clearly defined as a genetic defect of the insulin receptor (type A insulin resistance) (Taylor et al, 1990). The question raised therefore is whether, in some circumstances, hyperinsulinaemia may lead to the development of a polycystic ovary.…”