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Validation of Duchenne muscular dystrophy candidate modifiers using a CRISPR-Cas9-based approach in zebrafish.

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Název: Validation of Duchenne muscular dystrophy candidate modifiers using a CRISPR-Cas9-based approach in zebrafish.
Autoři: Lerma G, Ryhlick KR, Carraher OM, Beljan JC, Amacher SL
Zdroj: BioRxiv : the preprint server for biology [bioRxiv] 2025 May 20. Date of Electronic Publication: 2025 May 20.
Způsob vydávání: Journal Article; Preprint
Jazyk: English
Informace o časopise: Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE
Abstrakt: Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease for which there is no cure. There is a critical need for additional therapeutics. Human genome-wide association studies (GWAS) have identified candidate DMD genetic modifiers that could serve as therapeutic targets. Because many GWAS-identified single nucleotide polymorphisms (SNPs) lie in noncoding, putative regulatory regions, it can be challenging to identify which gene(s) are regulated by these SNPs and how gene expression is altered to modify disease severity even with extensive in silico modeling. We analyzed expression of zebrafish orthologs of putative DMD modifiers and showed almost all are comparably expressed in wild-type and dmd mutant zebrafish at three different stages of disease. To model decreased expression of candidate modifiers, we pursued a zebrafish CRISPR-based screening approach, which we validated by testing zebrafish orthologs of two extensively studied DMD modifiers, LTBP4 and THBS1. We then tested candidates from the most recent GWAS and demonstrate that galntl6, man1a1, etaa1a;etaa1b, and adamts17 are bona fide DMD modifiers. Our findings demonstrate the utility of zebrafish for DMD genetic modifier screening and characterizing modifier function.
Entry Date(s): Date Created: 20250606 Latest Revision: 20250606
Update Code: 20250606
PubMed Central ID: PMC12139783
DOI: 10.1101/2025.05.20.655139
PMID: 40475573
Databáze: MEDLINE
Popis
Abstrakt:Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease for which there is no cure. There is a critical need for additional therapeutics. Human genome-wide association studies (GWAS) have identified candidate DMD genetic modifiers that could serve as therapeutic targets. Because many GWAS-identified single nucleotide polymorphisms (SNPs) lie in noncoding, putative regulatory regions, it can be challenging to identify which gene(s) are regulated by these SNPs and how gene expression is altered to modify disease severity even with extensive in silico modeling. We analyzed expression of zebrafish orthologs of putative DMD modifiers and showed almost all are comparably expressed in wild-type and dmd mutant zebrafish at three different stages of disease. To model decreased expression of candidate modifiers, we pursued a zebrafish CRISPR-based screening approach, which we validated by testing zebrafish orthologs of two extensively studied DMD modifiers, LTBP4 and THBS1. We then tested candidates from the most recent GWAS and demonstrate that galntl6, man1a1, etaa1a;etaa1b, and adamts17 are bona fide DMD modifiers. Our findings demonstrate the utility of zebrafish for DMD genetic modifier screening and characterizing modifier function.
ISSN:2692-8205
DOI:10.1101/2025.05.20.655139