title: 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.
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.
authors.affiliation: Department of Internal Medicine II, Chiba University School of Medicine, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yagui
authors.forename: F
authors.initials: F
authors.lastname: Shimada
authors.forename: M
authors.initials: M
authors.lastname: Mimura
authors.forename: N
authors.initials: N
authors.lastname: Hashimoto
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Y
authors.initials: Y
authors.lastname: Tokuyama
authors.forename: K
authors.initials: K
authors.lastname: Nata
authors.forename: A
authors.initials: A
authors.lastname: Tohgo
authors.forename: F
authors.initials: F
authors.lastname: Ikehata
authors.forename: S
authors.initials: S
authors.lastname: Takasawa
authors.forename: H
authors.initials: H
authors.lastname: Okamoto
authors.forename: H
authors.initials: H
authors.lastname: Makino
authors.forename: Y
authors.initials: Y
authors.lastname: Saito
authors.forename: A
authors.initials: A
authors.lastname: Kanatsuka
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D019943:Amino Acid Substitution; D000818:Animals; D015703:Antigens, CD / Q000235:genetics* / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics* / Q000378:metabolism; D019556:COS Cells; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007564:Japan; D008297:Male; D008562:Membrane Glycoproteins; D008875:Middle Aged; D009097:Multienzyme Complexes / Q000235:genetics* / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense; D009244:NAD+ Nucleosidase / Q000235:genetics* / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D007328:Insulin; D008562:Membrane Glycoproteins; D009097:Multienzyme Complexes; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1