Mutations in FBXL4 cause mitochondrial encephalopathy and a disorder of mitochondrial DNA maintenance. R. W. Taylor1, J. W. Yarham1, A. Besse2, P. Wu2, E. A. Faqeih3, A. M. Al-Asmari3, M. A. M. Saleh3, W. Eyaid4, A. Hadeel4, L. He1, F. Smith5, S. Yau5, E. M. Simcox1, S. Miwa6, T. Donti2, K. K. Ab-Amero7, L.-J. Wong2, W. J. Craigen2, B. H. Graham2, K. L. Scott2, R. McFarland1, P. E. Bonnen2,8 1) Wellcome Trust Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, United Kingdom; 2) Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; 3) Section of Medical Genetics, Childrens Hospital, King Fahad Medical City, Riyadh, Saudi Arabia; 4) Department of Pediatrics, King Abdulaziz Medical City, King Saud Bin Abdulaziz University for Health & Science, Riyadh, Saudi Arabia; 5) DNA Laboratory, Guy's and St Thomas' Serco Pathology, Guy's Hospital, London, United Kingdom; 6) Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, United Kingdom; 7) Ophthalmic Genetics Laboratory, Department of Ophthalmology, College of Medicine, King Saud University, Riyadh, Saudi Arabia; 8) Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.

   Mitochondria play a key role in a variety of fundamental cellular processes including oxidative phosphorylation (OXPHOS), and due to their unique bi-genomic heritage, faithful organellar functioning is dependent upon the co-ordinated expression and interaction of both nuclear and mitochondrial-encoded gene products. Paediatric-onset mitochondrial disease has an estimated incidence of 1 in 5,000 but despite this common occurrence the molecular aetiology in individual cases often remains unknown, largely reflecting the large number of nuclear genes (~1400) which comprise the mitochondrial proteome. Mutations have been described in a number of nuclear genes involved in the maintenance of mitochondrial DNA (mtDNA), ultimately leading to secondary mtDNA abnormalities in clinically-affected tissues. Nuclear genetic disorders causing mitochondrial DNA (mtDNA) depletion syndrome - early-onset childhood disorders characterised by a quantitative loss of mtDNA copy number in clinically-relevant tissues - show phenotypic and genetic heterogeneity. Through whole exome sequencing, we have identified recessive nonsense and splicing mutations in the FBXL4 gene segregating in unrelated consanguineous kindreds in which affected children present with a fatal encephalopathy, lactic acidosis and severe mtDNA depletion in muscle. We show that FBXL4 is an F-box protein that co-localises with mitochondria, and that loss-of-function and splice mutations in this protein result in a severe respiratory chain deficiency, loss of mitochondrial membrane potential and a disturbance of the dynamic mitochondrial network and nucleoid distribution in patient fibroblasts. Expression of the wild-type FBXL4 transcript in patient cell lines fully rescued the levels of mtDNA copy number, leading to a correction of the mitochondrial biochemical deficit. Together these data establish FBXL4 as a new mitochondrial disease gene with a possible role in maintaining mtDNA integrity and stability.

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