Haack 2010 Nat Genet

From Bioblast

Reference

Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H (2010) Exome sequencing identifies ACAD9 mutations as a cause of Complex I deficiency. Nat Genet 42: 1131-1134.

Link: PMID: 21057504

Authors: Haack TB, Danhauser K, Haberberger B, Hoser J, Strecker V, Boehm D, Uziel G, Lamantea E, Invernizzi F, Poulton J, Rolinski B, Iuso A, Biskup S, Schmidt T, Mewes HW, Wittig I, Meitinger T, Zeviani M, Prokisch H

Year: 2010

Journal: Nat Genet

Abstract

An isolated defect of respiratory 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.

Keywords: exome sequences; complex I deficiency

Labels: High-Resolution Respirometry: Oxygraph-2k Injuries and Adaptations: Mitochondrial Disease; Degenerative Disease and Defect, Genetic Defect; Knockdown; Overexpression Tissues and Cells: Fibroblast Enzymes: Complex I