Genotype-phenotype correlation in inherited severe insulin resistance

Hum Mol Genet. 2002 Jun 1;11(12):1465-75. doi: 10.1093/hmg/11.12.1465.


The insulin receptor is a ligand-activated tyrosine kinase. Mutations in the corresponding gene cause the rare inherited insulin-resistant disorders leprechaunism and Rabson-Mendenhall syndrome. Patients with the most severe syndrome, leprechaunism, have growth restriction, altered glucose homeostasis and early death (usually before 1 year of age). Rabson-Mendenhall syndrome is less severe, with survival up to 5-15 years of age. These disorders are transmitted as autosomal recessive traits. Here we report six new patients and correlate mutations in the insulin receptor gene with survival. Patients with leprechaunism were homozygous or compound heterozygous for mutations in the extracellular domain of the insulin receptor and their cells had markedly impaired insulin binding (<10% of controls). Mutations in their insulin receptor gene inserted premature stop codons (E124X, R372X, G650X, E665X and C682X), resulting in decreased levels of mature mRNA, or affected the extracellular domain of the receptor (R86P, A92V, DeltaN281, I898T and R899W). Three patients with Rabson-Mendenhall syndrome had at least one missense mutation in the intracellular domain of the insulin receptor (P970T, I1116T, R1131W and R1174W). Expression studies in CHO cells indicated that the R86P, A92V, DeltaN281, I898T, R899W and R1131W mutations markedly impaired insulin binding (<5% of control), while the P970T, I1116T and R1174W mutant receptors retained significant insulin-binding activity. These results indicate that mutations in the insulin receptor retaining residual insulin-binding correlate with prolonged survival in our series of patients with extreme insulin resistance.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Substitution
  • Animals
  • CHO Cells
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Codon, Nonsense
  • Cricetinae
  • Female
  • Fibroblasts
  • Humans
  • Infant
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Male
  • Molecular Sequence Data
  • Mutation, Missense*
  • Phenotype
  • Receptor, Insulin / genetics*
  • Receptor, Insulin / metabolism


  • Codon, Nonsense
  • Insulin
  • Receptor, Insulin

Associated data

  • GENBANK/GM003348
  • GENBANK/GM005756
  • OMIM/246200
  • OMIM/262190