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Mutations in NDUFAF3 (C3ORF60), Encoding an NDUFAF4 (C6ORF66)-Interacting Complex I Assembly Protein, Cause Fatal Neonatal Mitochondrial Disease |
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| Authors: | Ann Saada Rutger O. Vogel Saskia J. Hoefs Hans J. Wessels Hanka Venselaar Flora Barghuti Mordechai Shohat Jan A.M. Smeitink Leo G. Nijtmans |
| Affiliation: | 1 Metabolic Disease Unit, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel 2 Nijmegen Centre for Mitochondrial Disorders, Department of Pediatrics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands 3 Nijmegen Centre for Mitochondrial Disorders, Department of Membrane Biochemistry, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands 4 Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen Medical Centre, Geert Grooteplein 10, 6500 HB, Nijmegen, The Netherlands 5 Al-Mustaqbal Hospital, P.O. Box 3921, Al-Bireh, Al-Balou, Ramallah 98700, Palestinian Authority 6 Genetics Institute, Assaf Harofeh Medical Center, Zerifin 70300, Israel 7 Department of Pediatrics and Genetics, The Raphael Recanati Genetic Institute, Rabin and Schneider Medical Centers, Petah Tikva 49100, Israel |
| 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. |
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