Diabetologia

, Volume 41, Issue 9, pp 1024–1028

A missense mutation in the CD38 gene, a novel factor for insulin secretion: association with Type II diabetes mellitus in Japanese subjects and evidence of abnormal function when expressed in vitro

Authors

  • K. Yagui
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
  • F. Shimada
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
  • M. Mimura
    • Department of Internal Medicine, Chiba Rousai Hospital, Ichihara, Japan
  • N. Hashimoto
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
  • Y. Suzuki
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
  • Y. Tokuyama
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
  • K. Nata
    • Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan
  • A. Tohgo
    • Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan
  • F. Ikehata
    • Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan
  • S. Takasawa
    • Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan
  • H. Okamoto
    • Department of Biochemistry, Tohoku University School of Medicine, Sendai, Japan
  • H. Makino
    • Department of Laboratory Medicine, Ehime University School of Medicine, Shigenobu, Japan
  • Y. Saito
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
  • A. Kanatsuka
    • Department of Internal Medicine II, Chiba University School of Medicine, Chiba, Japan
Originals

DOI: 10.1007/s001250051026

Cite this article as:
Yagui, K., Shimada, F., Mimura, M. et al. Diabetologia (1998) 41: 1024. doi:10.1007/s001250051026

Summary

Cyclic adenosine 5′diphosphate-ribose (cADPR) is thought to have a second messenger role in insulin secretion through mobilisation of Ca2 +. As human lymphocyte antigen CD38 has both ADP-ribosyl cyclase and cADPR hydrolase activity, it may be important in glucose-induced insulin secretion in islets. Thirty one randomly selected Japanese patients with Type II diabetes mellitus who had first-degree and/or second-degree relative(s) with Type II diabetes mellitus were screened for mutations of this gene using single-stranded conformation polymorphism. Two variant patterns in exon 3 and exon 4 of the CD38 gene were identified. The variant in exon 3 resulted in an amino acid substitution from Arg140 (CGG) to Trp (TGG). The Arg140Trp mutation was observed in 4 of 31 patients, and allele frequencies were significantly different in patients and the control subjects (p = 0.004). One patient with this mutation has two missense mutations on beta cell/liver glucose transporter (GLUT2) gene; her mother, who has impaired glucose tolerance, also has this mutation on the CD38 gene and one missense mutation on the GLUT2 gene. Enzyme activity studies using COS-7 cells expressing the Arg140Trp mutation showed a reduction in ADP-ribosyl cyclase and cADPR hydrolase activity of around 50 %. The Arg140Trp mutation on CD38 thus appears to contribute to the development of Type II diabetes mellitus via the impairment of glucose-induced insulin secretion in the presence of other genetic defects. [Diabetologia (1998) 41: 1024–1028]

Keywords CD38 genesusceptibilitymissense mutationType II diabetes mellituscyclic ADP-riboseADP-ribosyl cyclasecyclic ADP-ribose hydrolase
Download to read the full article text

Copyright information

© Springer-Verlag Berlin Heidelberg 1998