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Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy.

Fassone E., Taanman J.W., Hargreaves I.P., Sebire N.J., Cleary M.A., Burch M., Rahman S.

BACKGROUND:Hypertrophic cardiomyopathy (HCM) is frequently fatal in infancy. Mitochondrial disease causing infantile HCM is characterised by extreme biochemical and genetic heterogeneity, but deficiency of respiratory chain complex I is observed relatively frequently. Identification of the precise genetic basis has prognostic implications for the likelihood of neurological involvement. OBJECTIVE:The authors' objective is to report two heterozygous missense mutations in the NDUFAF1 gene as a cause of fatal infantile HCM in a patient with isolated complex I deficiency. METHODS:The authors investigated a cohort of 30 paediatric patients with complex I deficiency using biochemical and genetic approaches. The patients were clinically heterogeneous; phenotypes included HCM, Leigh syndrome, other encephalomyopathies and multisystem disease. Complex I assembly was evaluated using Blue Native polyacrylamide gel electrophoresis. RESULTS:Sequence analysis of NDUFAF1 revealed compound heterozygous missense mutations (c.631C>T;p.Arg211Cys and c.733G>A;p.Gly245Arg) in one patient with fatal infantile HCM. These changes were absent in 240 ethnically matched control alleles. No NDUFAF1 mutations were observed in the remaining patients. Functional studies demonstrated a severe reduction in NDUFAF1 protein in Western blots of patient fibroblasts and accumulation of abnormal complex I assembly intermediates on Blue Native polyacrylamide gel electrophoresis. CONCLUSIONS:The authors report a case of fatal infantile HCM caused by missense mutations in NDUFAF1 associated with complex I misassembly. Establishing a genetic diagnosis in mitochondrial cardiomyopathy is challenging and achieved in only a minority of cases because of complex genetics. A precise genetic diagnosis is important to provide accurate prognostic and genetic counselling advice regarding recurrence risks and to guide future reproductive options.

J. Med. Genet. 48:691-697(2011) [PubMed] [Europe PMC]

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