Reduced mRNA and a nonsense mutation in the insulin-receptor gene produce heritable severe insulin resistance

Am J Hum Genet. 1992 May;50(5):998-1007.


Leprechaunism is an autosomal recessive syndrome of severe insulin resistance and is characterized by intrauterine growth restriction, acanthosis nigricans, hirsutism, and loss of glucose homeostasis. Here we report a new female patient of Hispanic and Afro-American descent whose fibroblasts and lymphoblasts had markedly impaired insulin binding (less than 10% of that in controls). Insulin binding to lymphoblasts established from both unrelated parents was partially impaired. Insulin-like growth factor-I (IGF-I) and epidermal growth factor (EGF) binding to the patient's fibroblasts were within the normal range. Insulin stimulation of receptor autophosphorylation and kinase activity was markedly reduced in the patient's fibroblasts. The patient's fibroblasts had both a reduced number of immunoreactive insulin receptor (6% of those in controls) and concomitantly reduced amounts of insulin-receptor mRNA, suggesting that both mutations inherited by the patient reduced insulin-receptor mRNA. Sequencing of the insulin-receptor gene and cDNA indicated that the patient was heterozygous for a paternally derived mutation at bp 1333, converting Arg372 to a STOP codon. This nonsense mutation was observed in the insulin-receptor gene, but not in cDNA, indicating reduced amounts of mRNA for the allele containing this mutation. The coding sequence of the maternally inherited insulin-receptor allele was normal. Both the marked reduction in insulin-receptor mRNA in the compound heterozygous fibroblasts of the proband and the partially reduced insulin binding in maternal cells suggest that the maternally derived mutation is located in an insulin-receptor gene sequence that controls cellular mRNA content.

Publication types

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

MeSH terms

  • African Continental Ancestry Group / genetics
  • Base Sequence
  • Blotting, Northern
  • Cells, Cultured
  • Epidermal Growth Factor / metabolism
  • Female
  • Growth Disorders / genetics*
  • Heterozygote
  • Humans
  • Infant
  • Insulin / metabolism
  • Insulin Resistance / genetics*
  • Insulin-Like Growth Factor I / metabolism
  • Molecular Sequence Data
  • Mutation / genetics
  • Phosphorylation
  • Phosphotransferases / metabolism
  • RNA, Messenger / genetics*
  • Receptor, Insulin / genetics*
  • Receptor, Insulin / metabolism


  • Insulin
  • RNA, Messenger
  • Epidermal Growth Factor
  • Insulin-Like Growth Factor I
  • Phosphotransferases
  • Receptor, Insulin