Pathogenic Variants in the Myosin Chaperone UNC-45B Cause Progressive Myopathy with Eccentric Cores.
Adolescent
Adult
Alleles
Animals
Caenorhabditis elegans
Caenorhabditis elegans Proteins
/ genetics
Female
Genetic Variation
Humans
Loss of Function Mutation
Male
Molecular Chaperones
/ genetics
Muscle, Skeletal
/ pathology
Muscular Diseases
/ genetics
Mutation, Missense
Myofibrils
Myosins
Sarcomeres
/ metabolism
Sequence Analysis, RNA
Transgenes
Exome Sequencing
Young Adult
C. elegans
UNC-45
UNC45B
chaperone
core myopathy
muscle
myofibrillar
myosin
sarcomere
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:
03 12 2020
03 12 2020
Historique:
received:
15
06
2020
accepted:
03
11
2020
pubmed:
21
11
2020
medline:
13
1
2021
entrez:
20
11
2020
Statut:
ppublish
Résumé
The myosin-directed chaperone UNC-45B is essential for sarcomeric organization and muscle function from Caenorhabditis elegans to humans. The pathological impact of UNC-45B in muscle disease remained elusive. We report ten individuals with bi-allelic variants in UNC45B who exhibit childhood-onset progressive muscle weakness. We identified a common UNC45B variant that acts as a complex hypomorph splice variant. Purified UNC-45B mutants showed changes in folding and solubility. In situ localization studies further demonstrated reduced expression of mutant UNC-45B in muscle combined with abnormal localization away from the A-band towards the Z-disk of the sarcomere. The physiological relevance of these observations was investigated in C. elegans by transgenic expression of conserved UNC-45 missense variants, which showed impaired myosin binding for one and defective muscle function for three. Together, our results demonstrate that UNC-45B impairment manifests as a chaperonopathy with progressive muscle pathology, which discovers the previously unknown conserved role of UNC-45B in myofibrillar organization.
Identifiants
pubmed: 33217308
pii: S0002-9297(20)30399-2
doi: 10.1016/j.ajhg.2020.11.002
pmc: PMC7820787
pii:
doi:
Substances chimiques
Caenorhabditis elegans Proteins
0
Molecular Chaperones
0
UNC45B protein, human
0
unc-45 protein, C elegans
0
Myosins
EC 3.6.4.1
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1078-1095Informations de copyright
Copyright © 2020. Published by Elsevier Inc.
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