Journal
HUMAN MOLECULAR GENETICS
Volume 28, Issue 22, Pages 3766-3776Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddz202
Keywords
-
Funding
- Kidney Research UK
- Northern Counties Kidney Research Fund
- Wellcome Centre for Mitochondrial Research [203105/Z/16/Z]
- Medical Research Council (MRC) International Centre for Genomic Medicine in Neuromuscular Disease, Mitochondrial Disease Patient Cohort (UK) [G0800674]
- UK NIHR Biomedical Research Centre for Ageing and Age-related disease award
- MRC/EPSRC Molecular Pathology Node
- Lily Foundation
- UK NHS Highly Specialised Service for Rare Mitochondrial Disorders of Adults and Children
- Wellcome Trust [212219/Z/18/Z]
- Medical Research Council Mitochondrial Biology Unit [MC_UU_00015/9]
- Evelyn Trust
- National Institute for Health Research (NIHR) Biomedical Research Centre based at Cambridge University Hospitals NHS Foundation Trust and the University of Cambridge
- Telethon [GGP15041]
- Medical Research Council [MC_UP_1501/2, MC_UU_00015/9] Funding Source: researchfish
- Wellcome Trust [212219/Z/18/Z] Funding Source: researchfish
- Wellcome Trust [212219/Z/18/Z] Funding Source: Wellcome Trust
- MRC [MC_UU_00015/8, MC_UU_00015/9, G0800674, MR/L016354/1] Funding Source: UKRI
Ask authors/readers for more resources
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 Bjornstad 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available