Sequence variants in the pancreatic islet beta-cell inwardly rectifying K+ channel Kir6.2 (Bir) gene: identification and lack of role in Caucasian patients with NIDDM.
Signals derived from the metabolism of glucose in pancreatic beta-cells lead to insulin secretion via the closure of ATP-sensitive K+ channels (KATP). The cloning of the gene encoding the beta-cell inward rectifier Kir6.2 (Bir), a subunit of the beta-cell KATP channel, provided the opportunity to look for mutations in this gene that might contribute to the impaired insulin secretion of NIDDM. By single-strand conformational polymorphism (SSCP) analysis on 35 Northern-European Caucasian patients with NIDDM, six sequence variants were detected: Glu10gag-->Lys10aag (E1OK), Glu23gag-->Lys23aag (E23K), Leu270ctg-->Val270gtg (L270V), Ile337atc-->Val337gtc (I337V), and two silent mutations. Allelic frequencies for the missense variants were compared between the NIDDM group (n = 306) and nondiabetic control subjects (n = 175) and did not differ between the two groups. Pairwise allelic associations indicated significant linkage disequilibrium between the variants in Kir6.2 and between them and a nearby pancreatic beta-cell sulfonylurea receptor (SUR1) missense variant (S1370A), but these linkage disequilibria did not differ between the NIDDM and control groups. The results of these studies thus revealed that mutations in the coding region of Kir6.2 1) were not responsible for the previously noted association of the SUR1 variants with NIDDM (Inoue H et al., Diabetes 45:825-831, 1996) and 2) did not contribute to the impaired insulin secretion characteristic of NIDDM in Caucasian patients.
Inoue
H
H
Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Ferrer
J
J
Warren-Perry
M
M
Zhang
Y
Y
Millns
H
H
Turner
R C
RC
Elbein
S C
SC
Hampe
C L
CL
Suarez
B K
BK
Inagaki
N
N
Seino
S
S
Permutt
M A
MA
D017931:DNA Primers; D004262:DNA Restriction Enzymes; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005091:Exons; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D017354:Point Mutation; D012150:Polymorphism, Restriction Fragment Length; D018807:Polymorphism, Single-Stranded Conformational; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D012016:Reference Values; D006113:United Kingdom; D014589:Utah; D044465:White People / Q000235:genetics*
D017931:DNA Primers; D007328:Insulin; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D004262:DNA Restriction Enzymes