Work

Zebrafish as a model for Catel–Manzke syndrome—identification and characterization of the zebrafish TGDS ortholog

Year: 2025

Type: article

Abstract: Catel–Manzke syndrome (CMS) is a rare genetic disorder associated with mutations in the TDP‐glucose 4,6‐dehydratase ( TGDS ) gene, the function of which in vertebrates remains unclear. This study investigated the zebrafish ortholog tgds to assess its suitability for modeling the disease. During development, the tgds transcript exhibits a conserved biphasic expression pattern with an initial maternal contribution followed by a second wave of expression after gastrulation. Recombinant zebrafish Tgds expressed in Escherichia coli demonstrated UDP‐D‐glucose 4,6‐dehydratase ( EC4.2.1.76 ) activity, similar to TGDS orthologs in lower eukaryotes, where it acts as the first step in the L‐rhamnose biosynthetic pathway. This finding suggests the presence of a yet unidentified pathway in vertebrates. Furthermore, CMS‐associated mutations in conserved residues significantly impair enzyme activity and stability. CRISPR/Cas9‐mediated F 0 knockout of tgds resulted in a range of developmental defects in zebrafish. In particular, craniofacial cartilage alterations, associated with a decrease in sulfate glycosaminoglycan content, mirrored some skeletal features observed in humans with CMS. These findings establish the zebrafish as a relevant model to further explore CMS pathogenesis and the in vivo function of tgds .

Source: FEBS Journal

DOI: 10.1111/febs.70307