Rapid generation of a sdhb loss-of-function zebrafish model for secreting pheochromocytomas and paragangliomas

Parisien-la Salle, Stefanie; Nobilleau, Fanny; da Silva Babinet, Alexandra; Lamontagne, Julien; Labrecque, Michel; Rampal, Bryce; Mas, Charline; Liao, Meijiang; Barragan Torres, Viviana Andrea; Corbeil, Gilles; Chatel-Chaix, Laurent ORCID: https://orcid.org/0000-0002-7390-8250; Dona, Margo; Tetreault, Martine; Bourdeau, Isabelle et Samarut, Eric (2025). Rapid generation of a sdhb loss-of-function zebrafish model for secreting pheochromocytomas and paragangliomas npj Genomic Medicine , vol. 10 , nº 59. pp. 1-11. DOI: 10.1038/s41525-025-00518-z.

Prévisualisation

PDF - Version publiée Disponible sous licence Creative Commons Attribution Non-commercial No Derivatives. Télécharger (3MB) | Prévisualisation

Résumé

Genotype plays a central role in the comprehensive management of pheochromocytomas and paragangliomas, highlighting the critical need for specific in vivo genetic models. Yet, animal models fall short of fully recapitulating the biological complexity of these tumours. We generated first-generation loss-of-function zebrafish models for sdhb, a canonical PPGL-associated gene, using CRISPR/Cas9. Sdhb-CRISPants exhibit increased heart rates, reduced swimming activity and premature death. In whole fish extracts, normetanephrine (NM), metanephrine (MN), and dopamine (DA) levels were about three times higher in sdhb CRISPants than in control larvae. In the bathing medium, NM and MN were also significantly elevated, along with 3-MT. Complementary metabolic and transcriptomic profiling revealed that sdhb CRISPants exhibit a clear signature of Complex II dysfunction and upregulation of genes involved in the hypoxia response, angiogenesis, stress response, and glycolysis. Our work validates the relevance of CRISPant zebrafish models to study the pathogenicity of PPGL-causing genetic variants in vivo.

Type de document:	Article
Informations complémentaires:	The Seahorse analyzer was acquired through a Young Investigator Infrastructure Grant from the Armand-Frappier Foundation and the Institut National de la Recherche Scientifique to LCC
Mots-clés libres:	Genomic engineering; Functional genomics; Mutagenesis
Centre:	Centre INRS-Institut Armand Frappier
Date de dépôt:	16 juin 2026 14:49
Dernière modification:	16 juin 2026 14:49
URI:	https://espace.inrs.ca/id/eprint/16646

Gestion Actions (Identification requise)

Modifier la notice