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.
Unité de Recherches sur les Handicaps Génétiques de l'Enfant INSERM U12, Paris, France.
A
A
Rötig
V
V
Cormier
P
P
Chatelain
R
R
Francois
J M
JM
Saudubray
P
P
Rustin
A
A
Munnich
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