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

Lookup NU author(s): Dr Monika Olahova, Jack Collier, Dr Charlotte Alston, Dr Noel Edwards, Dr Langping He, Professor Patrick Chinnery, Professor Rita HorvathORCiD, Professor Robert Taylor, Professor John SayerORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2019. Published by Oxford University Press.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, cholestasis, iron overload, lactic acidosis and early death (GRACILE syndrome), and Björnstad syndrome, characterized 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 patient 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.

Publication metadata

Author(s): Olahova M, Berti CC, Collier JJ, Alston CL, Jameson E, Jones SA, Edwards N, He L, Chinnery PF, Horvath R, Goffrini P, Taylor RW, Sayer JA

Publication type: Article

Publication status: Published

Journal: Human Molecular Genetics

Year: 2019

Volume: 28

Issue: 22

Pages: 3766-3776

Print publication date: 15/11/2019

Online publication date: 22/08/2019

Acceptance date: 12/08/2019

Date deposited: 23/01/2020

ISSN (print): 0964-6906

ISSN (electronic): 1460-2083

Publisher: Oxford University Press


DOI: 10.1093/hmg/ddz202

PubMed id: 31435670


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