Mitochondrial FAD-glycerophosphate dehydrogenase and G-protein-coupled inwardly rectifying K+ channel: No evidence for linkage in maturity-onset diabetes of the young or NIDDM.
Two genes that have potentially important regulatory roles in insulin secretion are both located on chromosome 2q24.1. G-protein-coupled muscarinic potassium channel (GIRK1) is an inwardly rectifying K+ channel that helps to maintain the resting potential and excitability of cells. Mitochondrial FAD-linked glycerophosphate dehydrogenase (m-GDH) catalyzes a rate-limiting step of the glycerol phosphate shuttle in pancreatic islets. Reduced m-GDH activity has been demonstrated in islets isolated from diabetic subjects compared with islets from nondiabetic control subjects and from the diabetic GK rat. To study the relationship between these candidate genes and NIDDM, we have examined a simple tandem-repeat polymorphism (STRP) close to both the KCN J3 (GIRK1) locus and the m-GDH locus. In a linkage study of three maturity-onset diabetes of the young (MODY) pedigrees, not linked to MODY1, MODY2, or MODY3, a cumulative score of - 9.6 at a recombination fraction of theta = 0 excluded linkage. In a population-association study, no linkage disequilibrium for the STRP was found between 190 unselected NIDDM patients and 60 geographically and age-matched white nondiabetic subjects (chi2 = 1.51 on 3 df, P = 0.68). Thus, mutations involving the genes for GIRK1 or FAD-glycerophosphate dehydrogenase are unlikely to cause MODY, and a common mutation in either gene is unlikely to contribute to NIDDM in whites. These data do not exclude mutations in some families or other ethnic groups.
Warren-Perry
M G
MG
Diabetes Research Laboratories, Radcliffe Infirmary, Oxford, U.K.
Stoffel
M
M
Saker
P J
PJ
Zhang
Y
Y
Brown
L J
LJ
MacDonald
M J
MJ
Turner
R C
RC
D000818:Animals; D001483:Base Sequence; D002874:Chromosome Mapping; D018244:Chromosomes, Artificial, Yeast; D002889:Chromosomes, Human, Pair 2; D017931:DNA Primers; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D008040:Genetic Linkage; D005993:Glycerolphosphate Dehydrogenase / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000201:enzymology; D008969:Molecular Sequence Data; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D011976:Receptors, Muscarinic / Q000235:genetics; D011995:Recombination, Genetic; D012016:Reference Values; D012091:Repetitive Sequences, Nucleic Acid
D017931:DNA Primers; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011976:Receptors, Muscarinic; D005993:Glycerolphosphate Dehydrogenase; C098831:glycerol-3-phosphate oxidase