A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes.
From a family of 16 diabetic patients with typical maternal inheritance, we investigated a 69-year-old woman with type 2 diabetes. The proband showed no major deletions in the mitochondrial DNA (mtDNA). Direct sequencing revealed 7 missense and 5 ribosomal RNA homoplasmic nucleotide substitutions when compared with the Cambridge Sequence and its recent revision. When compared with the control cybrid cells, the proband cybrid cells showed 6 nucleotide substitutions. Among these, 14577 T/C, which turned out to be 98.9% heteroplasmic, is a new missense substitution in the NADH dehydrogenase 6 gene. We also observed 2 other patients with 14577 T/C substitution from another group of 252 unrelated diabetic patients, whereas no individual from a group of 529 control subjects had 14577 T/C substitution. Furthermore, these 6 substitutions were in linkage disequilibrium. Mitochondrial respiratory chain complex I activity and O2 consumption rates of the proband cybrid cells, which were obtained by the fusion of mtDNA-deleted (rho0) HeLa cells and mtDNA from the proband, showed 64.5 and 61.5% reductions, respectively, compared with control cybrid cells. The present study strongly indicates that the new mtDNA mutation at 14577 T/C is probably a major pathogenic mutation for type 2 diabetes in this family.
Third Department of Internal Medicine, Yamanashi Medical University, Tamaho, Japan. tawatam@res.yamanashi-med.ac.jp
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M
Tawata
J I
JI
Hayashi
K
K
Isobe
E
E
Ohkubo
M
M
Ohtaka
J
J
Chen
K
K
Aida
T
T
Onaya
D000368:Aged; D003573:Cytochrome b Group / Q000235:genetics; D004272:DNA, Mitochondrial / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology / Q000235:genetics*; D005260:Female; D018392:Genomic Imprinting; D006367:HeLa Cells; D006801:Humans; D006822:Hybrid Cells; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D020125:Mutation, Missense; D009245:NADH Dehydrogenase / Q000235:genetics*; D010101:Oxygen Consumption; D010375:Pedigree; D012335:RNA, Ribosomal / Q000235:genetics; D012336:RNA, Ribosomal, 16S / Q000235:genetics
D003573:Cytochrome b Group; D004272:DNA, Mitochondrial; D012335:RNA, Ribosomal; D012336:RNA, Ribosomal, 16S; C075526:RNA, ribosomal, 12S; D009245:NADH Dehydrogenase