Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease.
Mitochondrial complex I deficiency is the most prevalent and least understood disorder of the oxidative phosphorylation system. The genetic cause of many cases of isolated complex I deficiency is unknown because of insufficient understanding of the complex I assembly process and the factors involved. We performed homozygosity mapping and gene sequencing to identify the genetic defect in five complex I-deficient patients from three different families. All patients harbored mutations in the NDUFAF3 (C3ORF60) gene, of which the pathogenic nature was assessed by NDUFAF3-GFP baculovirus complementation in fibroblasts. We found that NDUFAF3 is a genuine mitochondrial complex I assembly protein that interacts with complex I subunits. Furthermore, we show that NDUFAF3 tightly interacts with NDUFAF4 (C6ORF66), a protein previously implicated in complex I deficiency. Additional gene conservation analysis links NDUFAF3 to bacterial-membrane-insertion gene cluster SecF/SecD/YajC and to C8ORF38, also implicated in complex I deficiency. These data not only show that NDUFAF3 mutations cause complex I deficiency but also relate different complex I disease genes by the close cooperation of their encoded proteins during the assembly process.
Saada
Ann
A
Metabolic Disease Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
Vogel
Rutger O
RO
Hoefs
Saskia J
SJ
van den Brand
Mariël A
MA
Wessels
Hans J
HJ
Willems
Peter H
PH
Venselaar
Hanka
H
Shaag
Avraham
A
Barghuti
Flora
F
Reish
Orit
O
Shohat
Mordechai
M
Huynen
Martijn A
MA
Smeitink
Jan A M
JA
van den Heuvel
Lambert P
LP
Nijtmans
Leo G
LG
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002148:Calmodulin-Binding Proteins / Q000235:genetics*; D003241:Consanguinity; D004252:DNA Mutational Analysis; D042967:Electron Transport Complex I / Q000235:genetics*; D004591:Electrophoresis, Polyacrylamide Gel; D017809:Fatal Outcome; D005260:Female; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D028361:Mitochondrial Diseases / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics*; D008957:Models, Genetic; D008969:Molecular Sequence Data; D010375:Pedigree; D017386:Sequence Homology, Amino Acid
D002148:Calmodulin-Binding Proteins; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; C541710:NDUFAF3 protein, human; C519296:NDUFAF4 protein, human; D042967:Electron Transport Complex I