Mutations in NDUFAF3 (C3ORF60), Encoding an NDUFAF4 (C6ORF66)-Interacting Complex I Assembly Protein, Cause Fatal Neonatal Mitochondrial Disease

Ann Saada, Rutger O. Vogel, Saskia J. Hoefs, Mariël A. van den Brand, Hans J. Wessels, Peter H. Willems, Hanka Venselaar, Avraham Shaag, Flora Barghuti, Orit Reish, Mordechai Shohat, Martijn A. Huynen, Jan A.M. Smeitink, Lambert P. van den Heuvel, Leo G. Nijtmans*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)718-727
Number of pages10
JournalAmerican Journal of Human Genetics
Volume84
Issue number6
DOIs
StatePublished - 12 Jun 2009
Externally publishedYes

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