Removal of maternal compensation reveals retinal-specific roles for Pomgnt1 in zebrafish

Genetic variants in Protein O-mannose N-acetylglucosaminyltransferase 1 (POMGNT1) result in a broad spectrum of disorders, ranging from severe congenital muscular dystrophy with brain and ocular malformations to non-syndromic retinitis pigmentosa. Despite POMGNT1's established role in the glycosylation of the transmembrane glycoprotein &alpha-dystroglycan (&alpha-DG), the mechanistic basis for this clinical variability remains poorly understood. Previous work in a zebrafish pomngt1 knock-out (KO) line identified retinal degeneration at 6 months post-fertilization (mpf). However, potential involvement of other tissues was not characterized, and compensation from maternal transcripts which can occur in the zebrafish oocyte was not tested. Here, we analyzed maternal-zygotic pomgnt1 KOs (MZKOs) to determine whether maternal compensation influences the onset and severity of pomgnt1-associated phenotypes. We assessed survival, gross morphology, locomotor activity, behavioral patterns, and retinal organization across multiple timepoints. MZKOs survived to adulthood and exhibited no morphological or locomotor deficits up to 5 mpf. Retinal abnormalities were found as early as 2 mpf in MZKOs, demonstrating that maternally provided factors of pomgnt1 delay the onset of retinal pathology. Additionally, MZKOs displayed a novel wall-hugging behavioral pattern that may be consistent with visual impairment or anxiety. These findings demonstrate a strong tissue-specific phenotype following loss of pomgnt1 in zebrafish showing evolutionary divergence in the necessity for Pomgnt1 function in the muscle. However, this strain provides a useful system for investigating the mechanisms underlying the retinal vulnerability observed in POMGNT1-related retinitis pigmentosa.