Comprehensive phenotypic characterization of an allelic series of zebrafish models of NEB-related nemaline myopathy.

alternative splicing muscle nebulin nemaline myopathy zebrafish

Journal

Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958

Informations de publication

Date de publication:
17 Mar 2024
Historique:
received: 11 01 2024
accepted: 20 02 2024
medline: 17 3 2024
pubmed: 17 3 2024
entrez: 17 3 2024
Statut: aheadofprint

Résumé

Nemaline myopathy (NM) is a rare congenital neuromuscular disorder characterized by muscle weakness and hypotonia, slow gross motor development, and decreased respiratory function. Mutations in at least twelve genes, all of each encode proteins that are either components of the muscle thin filament or regulate its length and stability, have been associated with NM. Mutations in Nebulin (NEB), a giant filamentous protein localized in the sarcomere, account for more than 50% of NM cases. At present, there remains a lack of understanding of whether NEB genotype influences nebulin function and NM-patient phenotypes. In addition, there is a lack of therapeutically tractable models that can enable drug discovery and address the current unmet treatment needs of patients. To begin to address these gaps, here we have characterized five new zebrafish models of NEB-related NM. These mutants recapitulate most aspects of NEB-based NM, showing drastically reduced survival, defective muscle structure, reduced contraction force, shorter thin filaments, presence of electron-dense structures in myofibers, and thickening of the Z-disks. This study represents the first extensive investigation of an allelic series of nebulin mutants, and thus provides an initial examination in pre-clinical models of potential genotype-phenotype correlations in human NEB patients. It also represents the first utilization of a set of comprehensive outcome measures in zebrafish, including correlation between molecular analyses, structural and biophysical investigations, and phenotypic outcomes. Therefore, it provides a rich source of data for future studies exploring the NM pathomechanisms, and an ideal springboard for therapy identification and development for NEB-related NM.

Identifiants

pubmed: 38493359
pii: 7630554
doi: 10.1093/hmg/ddae033
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Subventions

Organisme : NIH HHS
Pays : United States

Informations de copyright

© The Author(s) 2024. Published by Oxford University Press.

Auteurs

Lacramioara Fabian (L)

Genetics and Genome Biology Program, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.

Esmat Karimi (E)

Department of Cellular and Molecular Medicine, University of Arizona, 1007 E. Lowell Street, Tucson, AZ 85724, United States.

Gerrie P Farman (GP)

Department of Cellular and Molecular Medicine, University of Arizona, 1007 E. Lowell Street, Tucson, AZ 85724, United States.

Jochen Gohlke (J)

Department of Cellular and Molecular Medicine, University of Arizona, 1007 E. Lowell Street, Tucson, AZ 85724, United States.

Coen A C Ottenheijm (CAC)

Department of Physiology, Amsterdam University Medical Center (location VUMC), De Boelelaan 1108, Amsterdam 1081 HZ, The Netherlands.

Hendrikus L Granzier (HL)

Department of Cellular and Molecular Medicine, University of Arizona, 1007 E. Lowell Street, Tucson, AZ 85724, United States.

James J Dowling (JJ)

Genetics and Genome Biology Program, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
Division of Neurology, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8, Canada.
Departments of Paediatrics and Molecular Genetics, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.

Classifications MeSH