Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene

Mitochondrial complex I deficiency is the most common oxidative phosphorylation defect. Mutations have been detected in mitochondrial and nuclear genes, but the genetics of many patients remain unresolved and new genes are probably involved. In a consanguineous family, patients presented easy fatiga...

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Published in:	Brain (London, England : 1878) Vol. 134; no. Pt 1; pp. 210 - 219
Main Authors:	GERARDS, Mike, VAN DEN BOSCH, Bianca J. C, PROKISCH, Holger, RÖTIG, Agnès, DE COO, Irenaeus F. M, SMELTS, Hubert J. M, DANHAUSER, Katharina, SERRE, Valérie, VAN WEEGHEL, Michel, WANDERS, Ronald J. A, NICOLAES, Gerry A. F, SLUITER, Wim, SCHOONDERWOERD, Kees, SCHOLTE, Hans R
Format:	Journal Article
Language:	English
Published:	Oxford Oxford University Press 2011
Subjects:	Acyl-CoA Dehydrogenases - genetics Biological and medical sciences Diseases of striated muscles. Neuromuscular diseases Electron Transport Complex I - genetics Exercise Genotype Homozygote Humans Medical sciences Mitochondria - genetics Mitochondrial Diseases - drug therapy Mitochondrial Diseases - genetics Mutation Neurology Pedigree Phenotype Riboflavin - therapeutic use Riboflavin Nervous system diseases B-Vitamins Oxidative phosphorylation Deficiency ACAD9
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Summary:	Mitochondrial complex I deficiency is the most common oxidative phosphorylation defect. Mutations have been detected in mitochondrial and nuclear genes, but the genetics of many patients remain unresolved and new genes are probably involved. In a consanguineous family, patients presented easy fatigability, exercise intolerance and lactic acidosis in blood from early childhood. In muscle, subsarcolemmal mitochondrial proliferation and a severe complex I deficiency were observed. Exercise intolerance and complex I activity was improved by a supplement of riboflavin at high dosage. Homozygosity mapping revealed a candidate region on chromosome three containing six mitochondria-related genes. Four genes were screened for mutations and a homozygous substitution was identified in ACAD9 (c.1594 C>T), changing the highly conserved arginine-532 into tryptophan. This mutation was absent in 188 ethnically matched controls. Protein modelling suggested a functional effect due to the loss of a stabilizing hydrogen bond in an α-helix and a local flexibility change. To test whether the ACAD9 mutation caused the complex I deficiency, we transduced fibroblasts of patients with wild-type and mutant ACAD9. Wild-type, but not mutant, ACAD9 restored complex I activity. An unrelated patient with the same phenotype was compound heterozygous for c.380 G>A and c.1405 C>T, changing arginine-127 into glutamine and arginine-469 into tryptophan, respectively. These amino acids were highly conserved and the substitutions were not present in controls, making them very probably pathogenic. Our data support a new function for ACAD9 in complex I function, making this gene an important new candidate for patients with complex I deficiency, which could be improved by riboflavin treatment.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 ObjectType-Article-2 ObjectType-Feature-1
ISSN:	0006-8950 1460-2156
DOI:	10.1093/brain/awq273