Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency.
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.
Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Tobias B
TB
Haack
Katharina
K
Danhauser
Birgit
B
Haberberger
Jonathan
J
Hoser
Valentina
V
Strecker
Detlef
D
Boehm
Graziella
G
Uziel
Eleonora
E
Lamantea
Federica
F
Invernizzi
Joanna
J
Poulton
Boris
B
Rolinski
Arcangela
A
Iuso
Saskia
S
Biskup
Thorsten
T
Schmidt
Hans-Werner
HW
Mewes
Ilka
I
Wittig
Thomas
T
Meitinger
Massimo
M
Zeviani
Holger
H
Prokisch
D044944:Acyl-CoA Dehydrogenases / Q000737:chemistry / Q000235:genetics*; D000595:Amino Acid Sequence; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000378:metabolism; D015180:Electrophoresis, Gel, Two-Dimensional; D005091:Exons / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005816:Genetic Complementation Test; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D012256:Riboflavin / Q000494:pharmacology; D017422:Sequence Analysis, DNA; D014161:Transduction, Genetic
D044944:Acyl-CoA Dehydrogenases; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I; D012256:Riboflavin