Mutations in Insulin-Receptor Gene in Insulin-Resistant Patients
Authors: Taylor Simeon I , Kadowaki Takashi , Kadowaki Hiroko , Accili Domenico , Cama Alessandro , McKeon Catherine 
Published: March 2007

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 &gt;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 c/s-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 a-subunit of the insulin receptor. This mutation retards t 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 α-subunit and the entirβ-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 α-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. Some patients have a normal number of receptors on their cell surface, but there is a defect in receptor function. A mutation has been described in the tetrabasic amino acid sequence separating the α- from the β-subunit. This mutation, identified in two sisters from a consanguineous pedigree, inhibits the cleavage of the receptor precursor into separate subunits. The uncleaved receptor has a decreased affinity to bind insulin. An insulin-resistant patient has been identified in whose insulin receptors there is a defect in tyrosine kinase activity due to a mutation that substitutes valine for glycine-1008, the third glycine in the conserved Gly-X-Gly-X-X-Gly motif in the ATP-binding domain of the β-subunit of the insulin receptor. The patient is heterozygous for this mutation. All of the mutations in the insulin-receptor gene that have been identified so far have been detected in patients with rare clinical syndromes associated with extreme insulin resistance. Recent advances in recombinant DNA technology have greatly simplified the task of detecting mutations. Thus, it should soon be possible to determine the prevalence of mutations in the insulin-receptor gene. These studies will also answer the question of whether mutations in the insulin-receptor gene contribute to the pathogenesis of insulin resistance with common forms of NIDDM.