title: A novel NDUFA1 mutation leads to a progressive mitochondrial complex I-specific neurodegenerative disease.
abstract: 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.
authors.affiliation: Center for Molecular and Mitochondrial Medicine and Genetics (MAMMAG), University of California, 2034 Hewitt Hall, Irvine, CA 92697-3940, USA.
authors.forename: Prasanth
authors.initials: P
authors.lastname: Potluri
authors.forename: Antonio
authors.initials: A
authors.lastname: Davila
authors.forename: Eduardo
authors.initials: E
authors.lastname: Ruiz-Pesini
authors.forename: Dan
authors.initials: D
authors.lastname: Mishmar
authors.forename: Sean
authors.initials: S
authors.lastname: O'Hearn
authors.forename: Saege
authors.initials: S
authors.lastname: Hancock
authors.forename: Mariella
authors.initials: M
authors.lastname: Simon
authors.forename: Immo E
authors.initials: IE
authors.lastname: Scheffler
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Wallace
authors.forename: Vincent
authors.initials: V
authors.lastname: Procaccio
mesh_terms: 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
chemical_list: D004272:DNA, Mitochondrial; D021122:Protein Subunits; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C118736:NDUFA1 protein, human