Mutations in the mitochondrial complex I assembly factor NDUFAF1 cause fatal infantile hypertrophic cardiomyopathy. Issue 10 (19th September 2011)

• Record Type: Journal Article
• Authors: Fassone, Elisa; Taanman, Jan-Willem; Hargreaves, Iain P; Sebire, Neil J; Cleary, Maureen A; Burch, Michael; Rahman, Shamima
• Is Part Of: Journal of medical genetics. Volume 48:Issue 10(2011)
• Page Start: 691
• Page End: 697
• Publication Date: 2011-09-19
• Subjects: Mitochondrial respiratory chain -- hypertrophic cardiomyopathy -- NADH:ubiquinone oxidoreductase -- complex I deficiency -- NDUFAF1 -- molecular genetics -- nutrition and metabolism -- neuromuscular disease -- muscle disease -- molecular genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2011-100340
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : 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.