Zebrafish gon4la mutants recapitulate human GON4L-related growth disorders and reveal novel metabolic organs abnormalities.

Biallelic mutations in human GON4L have been linked to short stature, craniofacial abnormalities, and microcephaly, yet the underlying mechanisms remain unclear. GON4L is a nuclear protein composed of a YY1AP1-like region, two PAH domains, and one SANT domain, all implicated in transcriptional or chromatin regulation. Here, we define the function of Gon4la (a zebrafish ortholog of human GON4L) in post-embryonic growth and tissue homeostasis. We generated three gon4la mutant lines using CRISPR-Cas9, each predicted to express truncated proteins lacking the C-terminal PAH/SANT domains and differing in N-terminal YY1AP1-like region retention. All gon4la mutants displayed proportionate dwarfism with intestinal and pancreatic abnormalities, accompanied by expanded progenitor proliferation and impaired epithelial differentiation. Only mutants completely lacking the N-terminal YY1AP1-like region exhibited reduced igf1a expression, elevated growth hormone pathway activity, and increased mortality, consistent with endocrine dysregulation. Our findings demonstrate that distinct domains of Gon4la contribute differentially to systemic growth and metabolic organ homeostasis. Zebrafish gon4la mutants provide a tractable vertebrate model for dissecting mechanisms of GON4L-related developmental disorder, Li-Takada-Miyake syndrome (LTMS), and for functional testing of rare GON4L variants.