A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease.
Mitochondrial diseases have been shown to result from mutations in mitochondrial genes located in either the nuclear DNA (nDNA) or mitochondrial DNA (mtDNA). Mitochondrial OXPHOS complex I has 45 subunits encoded by 38 nuclear and 7 mitochondrial genes. Two male patients in a putative X-linked pedigree exhibiting a progressive neurodegenerative disorder and a severe muscle complex I enzyme defect were analyzed for mutations in the 38 nDNA and seven mtDNA encoded complex I subunits. The nDNA X-linked NDUFA1 gene (MWFE polypeptide) was discovered to harbor a novel missense mutation which changed a highly conserved glycine at position 32 to an arginine, shown to segregate with the disease. When this mutation was introduced into a NDUFA1 null hamster cell line, a substantial decrease in the complex I assembly and activity was observed. When the mtDNA of the patient was analyzed, potentially relevant missense mutations were observed in the complex I genes. Transmitochondrial cybrids containing the patient's mtDNA resulted in a mild complex I deficiency. Interestingly enough, the nDNA encoded MWFE polypeptide has been shown to interact with various mtDNA encoded complex I subunits. Therefore, we hypothesize that the novel G32R mutation in NDUFA1 is causing complex I deficiency either by itself or in synergy with additional mtDNA variants.
Potluri
Prasanth
P
Center for Molecular and Mitochondrial Medicine and Genetics (MAMMAG), University of California, 2034 Hewitt Hall, Irvine, CA 92697-3940, USA.
Davila
Antonio
A
Ruiz-Pesini
Eduardo
E
Mishmar
Dan
D
O'Hearn
Sean
S
Hancock
Saege
S
Simon
Mariella
M
Scheffler
Immo E
IE
Wallace
Douglas C
DC
Procaccio
Vincent
V
D000328:Adult; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D016466:CHO Cells; D002648:Child; D002675:Child, Preschool; D006224:Cricetinae; D003412:Cricetulus; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics; D018450:Disease Progression; D042967:Electron Transport Complex I / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008931:Mitochondria, Muscle / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000150:complications* / Q000235:genetics*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation / Q000235:genetics*; D009245:NADH Dehydrogenase / Q000737:chemistry / Q000235:genetics*; D019636:Neurodegenerative Diseases / Q000150:complications* / Q000235:genetics*; D010375:Pedigree; D021122:Protein Subunits / Q000235:genetics
D004272:DNA, Mitochondrial; D021122:Protein Subunits; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C118736:NDUFA1 protein, human