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Hum Mol Genet. 2019 Aug 22. pii: ddz202. doi: 10.1093/hmg/ddz202. [Epub ahead of print]

Molecular genetic investigations identify new clinical phenotypes associated with BCS1L-related mitochondrial disease.

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Wellcome Centre for Mitochondrial Research, Institute of Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK.
Department of Chemistry, Life Sciences and Environmental Sustainability, University of Parma, Parma, Italy.
Manchester Centre for Genomic Medicine, St. Mary's Hospital, Central Manchester NHS Trust, Manchester Academic Health Science Centre, Manchester, UK.
Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, NE1 3BZ, UK.
Medical Research Council Mitochondrial Biology Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XY, UK.
Department of Clinical Neurosciences, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
Renal Services, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE7 7DN UK.
NIHR Newcastle Biomedical Research Centre, Newcastle upon Tyne, NE4 5PL, UK.


BCS1L encodes a homolog of the Saccharomyces cerevisiae bcs1 protein, which has a known role in the assembly of Complex III of the mitochondrial respiratory chain. Phenotypes reported in association with pathogenic BCS1L variants, include Growth Retardation, Aminoaciduria, Chloestasis, Iron overload, Lactic acidosis and Early death (GRACILE syndrome) and Björnstad syndrome, characterised by abnormal flattening and twisting of hair shafts (pili torti) and hearing problems. Here we describe two patients harbouring biallelic variants in BCS1L; the first with a heterozygous variant c.166C>T, p.(Arg56*) together with a novel heterozygous variant c.205C>T, p.(Arg69Cys) and a second patient with a novel homozygous c.325C>T, p.(Arg109Trp) variant. The two patients presented with different phenotypes; the first patient presented as an adult with aminoaciduria, seizures, bilateral sensorineural deafness and learning difficulties. The second was an infant who presented with a classical GRACILE syndrome leading to death at 4 months of age. A decrease in BCS1L protein levels was seen in both patients and biochemical analysis of Complex III revealed normal respiratory chain enzyme activities in the muscle of both patients. A decrease in Complex III assembly was detected in the adult patient's muscle, whilst the paediatric patient displayed a combined mitochondrial respiratory chain defect in cultured fibroblasts. Yeast complementation studies indicate that the two missense variants, c.205C>T, p.(Arg69Cys) and c.325C>T, p.(Arg109Trp), impair the respiratory capacity of the cell. Together, these data support the pathogenicity of the novel BCS1L variants identified in our patients.


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