TRANSCRIPTOMIC STUDY OF A ZEBRAFISH MODEL TO INVESTIGATE THE PATHOPHYSIOLOGICAL MECHANISMS OF XIA-GIBBS SYNDROME

Abstract

The Xia-Gibbs syndrome (XGS, OMIM #615829) is a neurodevelopmental disorder caused by pathogenic variants in heterozygosity in the AHDC1 gene. The main clinical features of XGS include hypotonia, motor and speech delay, and intellectual disability. The pathophysiology of XGS is not fully understood, requiring additional functional studies. We developed a zebrafish (Danio rerio) model with a heterozygous loss-of-function mutation in the ahdc1 gene induced through the CRISPR-Cas9 technique (designated ahdc1dsao1 - ZDB-ALT-221025-2 - on zfin.org) (CARVALHO et al. 2023). Transcriptomic studies are relevant for identifying differentially expressed genes and associated gene networks, allowing for the proposition of altered biological pathways in the pathological state. Therefore, the present study aims to compare the transcriptomes of animals with three different genotypes (heterozygotes, homozygotes, and wild types for the ahdc1 mutation) at two different developmental stages. Specific objectives include the identification of transcripts with quantitative differences between genotypes in each stage, the identification of enriched biological pathways, and addressing questions related to laboratory hypotheses. This encompasses the involvement of the ahdc1 gene in cell cycle control pathways, myelination, appetite-satiety regulation, energy metabolism, as well as transcriptional changes in known genes associated with genetic disorders of neurodevelopment. Relevant observations will be assessed by RTqPCR for validation purposes.