Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency

被引：183

作者：

Haack, Tobias B. ^{[2
,3
]}

Danhauser, Katharina ^{[2
,3
]}

Haberberger, Birgit ^{[2
,3
]}

Hoser, Jonathan ^{[4
]}

Strecker, Valentina ^{[5
]}

Boehm, Detlef ^{[6
]}

Uziel, Graziella ^{[7
]}

Lamantea, Eleonora ^{[1
]}

Invernizzi, Federica ^{[1
]}

Poulton, Joanna ^{[8
]}

Rolinski, Boris ^{[9
]}

Iuso, Arcangela ^{[2
]}

Biskup, Saskia ^{[6
]}

Schmidt, Thorsten ^{[4
]}

Mewes, Hans-Werner ^{[4
,10
]}

Wittig, Ilka ^{[5
]}

Meitinger, Thomas ^{[2
,3
]}

Zeviani, Massimo ^{[1
]}

Prokisch, Holger ^{[2
,3
]}

机构：

[1] IRCCS Fdn, Neurol Inst Carlo Besta, Unit Mol Neurogenet, Milan, Italy

[2] German Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany

[3] Tech Univ Munich, Inst Human Genet, Munich, Germany

[4] Germany Res Ctr Environm Hlth, Helmholtz Zentrum Munchen, Inst Bioinformat & Syst Biol, Neuherberg, Germany

[5] Goethe Univ Frankfurt, Sch Med, Frankfurt, Germany

[6] CeGaT GmbH, Tubingen, Germany

[7] IRCCS Fdn, Neurol Inst Carlo Besta, Unit Child Neurol, Milan, Italy

[8] Univ Oxford, John Radcliffe Hosp, Nuffield Dept Obstet & Gynaecol, Womens Ctr, Oxford OX3 9DU, England

[9] Stadt Klinikum Munchen GmbH, Dept Klin Chem, Munich, Germany

[10] Tech Univ Munich, Freising Weihenstephan, Ctr Life & Food Sci, Chair Genome Oriented Bioinformat, Munich, Germany

来源：

NATURE GENETICS | 2010年 / 42卷 / 12期

基金：

英国医学研究理事会;

关键词：

BETA-OXIDATION; MITOCHONDRIAL; DIAGNOSIS; DATABASE; CAPTURE; CELLS; PAGE;

D O I：

10.1038/ng.706

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

An isolated defect of respiratory chain complex I activity is a frequent biochemical abnormality in mitochondrial disorders. Despite intensive investigation in recent years, in most instances, the molecular basis underpinning complex I defects remains unknown. We report whole-exome sequencing of a single individual with severe, isolated complex I deficiency. This analysis, followed by filtering with a prioritization of mitochondrial proteins, led us to identify compound heterozygous mutations in ACAD9, which encodes a poorly understood member of the mitochondrial acyl-CoA dehydrogenase protein family. We demonstrated the pathogenic role of the ACAD9 variants by the correction of the complex I defect on expression of the wildtype ACAD9 protein in fibroblasts derived from affected individuals. ACAD9 screening of 120 additional complex I-defective index cases led us to identify two additional unrelated cases and a total of five pathogenic ACAD9 alleles.

引用

页码：1131 / +

页数：5

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