Title: Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease
Authors: Saada, Ann ×
Vogel, Rutger O
Hoefs, Saskia J
van den Brand, Mariël A
Wessels, Hans J
Willems, Peter H
Venselaar, Hanka
Shaag, Avraham
Barghuti, Flora
Reish, Orit
Shohat, Mordechai
Huynen, Martijn A
Smeitink, Jan A M
van den Heuvel, Lambertus
Nijtmans, Leo G #
Issue Date: Jun-2009
Publisher: American Society of Human Genetics
Series Title: American Journal of Human Genetics vol:84 issue:6 pages:718-727
Abstract: 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.
ISSN: 0002-9297
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Non-KU Leuven Association publications
× corresponding author
# (joint) last author

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