A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism (original) (raw)

Summary

We report a homozygous missense mutation at position 1092 (substitution of glutamine for arginine) in the tyrosine kinase domain of the insulin receptor in a patient with leprechaunism associated with severe insulin resistance and intrauterine growth retardation. Site-directed mutagenesis as well as analyses of the patient's lymphocytes revealed that this mutation causes a marked decrease in tyrosine kinase activity of the insulin receptor without any defect in insulin binding, which causes severe defects in insulin-stimulated glucose transport, glycogen synthesis and DNA synthesis. Thus, this is the first homozygous mutation resulting in a selective-kinase defect of the insulin receptor. Interestingly, the parents who are cousins and are heterozygous for the mutation have type A insulin resistance syndrome. This correlation between genotype and phenotype in a single pedigree suggests that the severity of the mutation will determine the phenotype. Based upon this assumption, we have been successful in prenatal diagnosis of the fifth child. Furthermore, we have demonstrated the effectiveness of clinical administration of insulin-like growth factor-I (IGF-I) in this patient and in vitro analysis of the patient's skin fibroblasts, suggesting that IGF-I can compensate for insulin action via the IGF-I receptor in a patient almost lacking functional insulin receptors. [Diabetologia (1997) 40: 412–420]

Article PDF

Similar content being viewed by others

Author information

Authors and Affiliations

  1. Third Department of Internal Medicine, Faculty of Medicine, University of Tokyo, Tokyo, Japan, , , , , , JP
    Y. Takahashi, K. Momomura, Y. Yazaki & T. Kadowaki
  2. Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan, , , , , , JP
    H. Kadowaki & Y. Akanuma
  3. Saitama Children's Medical Center, Iwatsuki, Japan, , , , , , JP
    Y. Fukushima
  4. Tawam Hospital, Abu Dhabi, United Arab Emirates, , , , , , AE
    T. Orban
  5. Department of Obstetrics and Gynecology, Faculty of Medicine, University of Tokyo, Tokyo, Japan, , , , , , JP
    T. Okai & Y. Taketani

Authors

  1. Y. Takahashi
    You can also search for this author inPubMed Google Scholar
  2. H. Kadowaki
    You can also search for this author inPubMed Google Scholar
  3. K. Momomura
    You can also search for this author inPubMed Google Scholar
  4. Y. Fukushima
    You can also search for this author inPubMed Google Scholar
  5. T. Orban
    You can also search for this author inPubMed Google Scholar
  6. T. Okai
    You can also search for this author inPubMed Google Scholar
  7. Y. Taketani
    You can also search for this author inPubMed Google Scholar
  8. Y. Akanuma
    You can also search for this author inPubMed Google Scholar
  9. Y. Yazaki
    You can also search for this author inPubMed Google Scholar
  10. T. Kadowaki
    You can also search for this author inPubMed Google Scholar

Additional information

Received: 25 September 1996 and in revised form: 10 December 1996

Rights and permissions

About this article

Cite this article

Takahashi, Y., Kadowaki, H., Momomura, K. et al. A homozygous kinase-defective mutation in the insulin receptor gene in a patient with leprechaunism.Diabetologia 40, 412–420 (1997). https://doi.org/10.1007/s001250050695

Download citation