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

K. Yagui, F. Shimada, M. Mimura, N. Hashimoto, Y. Suzuki, Y. Tokuyama, K. Nata, A. Tohgo, F. Ikehata, S. Takasawa, H. Okamoto, H. Makino, Y. Saito, A. Kanatsuka

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57 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)1024-1028
Number of pages5
JournalDiabetologia
Volume41
Issue number9
DOIs
Publication statusPublished - 1998

Keywords

  • ADP-ribosyl cyclase
  • CD38 gene
  • Cyclic ADP-ribose
  • Cyclic ADP-ribose hydrolase
  • Missense mutation
  • Susceptibility
  • Type II diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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