Caenorhabditis elegans models for striated muscle disorders caused by missense variants of human LMNA.
Journal
PLoS genetics
ISSN: 1553-7404
Titre abrégé: PLoS Genet
Pays: United States
ID NLM: 101239074
Informations de publication
Date de publication:
08 2023
08 2023
Historique:
received:
10
04
2023
accepted:
01
08
2023
revised:
07
09
2023
medline:
8
9
2023
pubmed:
25
8
2023
entrez:
25
8
2023
Statut:
epublish
Résumé
Striated muscle laminopathies caused by missense mutations in the nuclear lamin gene LMNA are characterized by cardiac dysfunction and often skeletal muscle defects. Attempts to predict which LMNA variants are pathogenic and to understand their physiological effects lag behind variant discovery. We created Caenorhabditis elegans models for striated muscle laminopathies by introducing pathogenic human LMNA variants and variants of unknown significance at conserved residues within the lmn-1 gene. Severe missense variants reduced fertility and/or motility in C. elegans. Nuclear morphology defects were evident in the hypodermal nuclei of many lamin variant strains, indicating a loss of nuclear envelope integrity. Phenotypic severity varied within the two classes of missense mutations involved in striated muscle disease, but overall, variants associated with both skeletal and cardiac muscle defects in humans lead to more severe phenotypes in our model than variants predicted to disrupt cardiac function alone. We also identified a separation of function allele, lmn-1(R204W), that exhibited normal viability and swimming behavior but had a severe nuclear migration defect. Thus, we established C. elegans avatars for striated muscle laminopathies and identified LMNA variants that offer insight into lamin mechanisms during normal development.
Identifiants
pubmed: 37624850
doi: 10.1371/journal.pgen.1010895
pii: PGENETICS-D-23-00419
pmc: PMC10484454
doi:
Substances chimiques
Lamin Type A
0
LMNA protein, human
0
LMN-1 protein, C elegans
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e1010895Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM129374
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM134859
Pays : United States
Informations de copyright
Copyright: © 2023 Gregory et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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