Bi-Allelic UQCRFS1 Variants Are Associated with Mitochondrial Complex III Deficiency, Cardiomyopathy, and Alopecia Totalis.
Q-cycle
Rieske iron-sulfur protein
alopecia
cardiomyopathy
microscale respiratory
mitochondrial complex III deficiency
mitochondrial import sequence
mitochondriopathy
mutation
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
02 01 2020
02 01 2020
Historique:
received:
16
07
2019
accepted:
05
12
2019
pubmed:
31
12
2019
medline:
18
4
2020
entrez:
30
12
2019
Statut:
ppublish
Résumé
Isolated complex III (CIII) deficiencies are among the least frequently diagnosed mitochondrial disorders. Clinical symptoms range from isolated myopathy to severe multi-systemic disorders with early death and disability. To date, we know of pathogenic variants in genes encoding five out of 10 subunits and five out of 13 assembly factors of CIII. Here we describe rare bi-allelic variants in the gene of a catalytic subunit of CIII, UQCRFS1, which encodes the Rieske iron-sulfur protein, in two unrelated individuals. Affected children presented with low CIII activity in fibroblasts, lactic acidosis, fetal bradycardia, hypertrophic cardiomyopathy, and alopecia totalis. Studies in proband-derived fibroblasts showed a deleterious effect of the variants on UQCRFS1 protein abundance, mitochondrial import, CIII assembly, and cellular respiration. Complementation studies via lentiviral transduction and overexpression of wild-type UQCRFS1 restored mitochondrial function and rescued the cellular phenotype, confirming UQCRFS1 variants as causative for CIII deficiency. We demonstrate that mutations in UQCRFS1 can cause mitochondrial disease, and our results thereby expand the clinical and mutational spectrum of CIII deficiencies.
Identifiants
pubmed: 31883641
pii: S0002-9297(19)30469-0
doi: 10.1016/j.ajhg.2019.12.005
pmc: PMC7042493
pii:
doi:
Substances chimiques
Iron-Sulfur Proteins
0
UQCRFS1 protein, human
0
Electron Transport Complex III
EC 7.1.1.8
Types de publication
Case Reports
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
102-111Subventions
Organisme : Austrian Science Fund FWF
ID : I 2741
Pays : Austria
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
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