Deletion of mitochondrial DNA in a case of early-onset diabetes mellitus, optic atrophy, and deafness (Wolfram syndrome, MIM 222300).
The Wolfram syndrome (MIM 222300) is a disease of unknown origin consisting of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness. Here we report on a generalized deficiency of the mitochondrial respiratory enzyme activities in skeletal muscle and lymphocyte homogenate of a girl suffering from the Wolfram syndrome. In addition, we provide evidence for a 7.6-kilobase pair heteroplasmic deletion (spanning nucleotides 6465-14135) of the mitochondrial DNA in the two tissues and show that directly repeated sequences (11 bp) were present in the wild-type mitochondrial genome at the boundaries of the deletion. Neither of the patient's parents was found to bear rearranged molecules. This study supports the view that a respiratory chain defect can present with insulin-dependent diabetes mellitus as the onset symptom. It also suggests that a defect of oxidative phosphorylation should be considered when investigating other cases of Wolfram syndrome, especially because this syndrome fulfills the criteria for a genetic defect of the mitochondrial energy supply: (a) an unexplained association of symptoms (b) with early onset and rapidly progressive course, (c) involving seemingly unrelated organs and tissues.
Rötig
A
A
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U12, Paris, France.
Cormier
V
V
Chatelain
P
P
Francois
R
R
Saudubray
J M
JM
Rustin
P
P
Munnich
A
A
D000293:Adolescent; D001483:Base Sequence; D015139:Blotting, Southern; D004272:DNA, Mitochondrial / Q000235:genetics*; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006801:Humans; D008214:Lymphocytes / Q000201:enzymology; D008969:Molecular Sequence Data; D009132:Muscles / Q000201:enzymology; D009245:NADH Dehydrogenase / Q000378:metabolism; D009838:Oligodeoxyribonucleotides; D017384:Sequence Deletion; D013384:Succinate Cytochrome c Oxidoreductase / Q000378:metabolism; D014929:Wolfram Syndrome / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology
D004272:DNA, Mitochondrial; D009838:Oligodeoxyribonucleotides; D013384:Succinate Cytochrome c Oxidoreductase; D009245:NADH Dehydrogenase; D003576:Electron Transport Complex IV