Functional study of Xia-Gibbs syndrome: characterization and phenotypic analysis of the ahdc1dsao1 zebrafish model

• Grant number: 23/16666-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: February 01, 2024
• End date: June 30, 2025
• Field of knowledge: Biological Sciences - Genetics - Human and Medical Genetics
• Principal Investigator: Ana Cristina Victorino Krepischi
• Grantee: Sofia de Oliveira Farias
• Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Intellectual disability (ID) is one of the most common neurodevelopmental disorders, affecting approximately 1% of the population worldwide. The use of animal models to study various clinical conditions associated with ID is essential for elucidating the pathophysiological mechanisms. XiaGibbs syndrome (XGS) is a rare syndromic form of autosomal dominant ID. Patients with XGScommonly present, in addition to ID, features such as hypotonia, global developmental delay, structural brain anomalies and facial dysmorphisms. XGS occurs due to heterozygous pathogenic variants in the AHDC1 gene. The molecular mechanism leading to XGS and the function of AHDC1 in neurodevelopment are still under investigation, as there are many gaps in knowledge. The development of functional studies is, therefore, essential for understanding the pathophysiology of this syndrome. Danio rerio (zebrafish) is a species commonly used to study human genetic diseases and we previously developed an animal model for XGS with an indel-type variant in the ahdc1 gene (ahdc1dsao1). The central objective of the proposed project is to deepen the knowledge about XGS; however, a robust animal model must present characteristics that overlap the phenotypical manifestation in humans. Thus, to validate the adch1dsao1 model for XGS, the present study proposes the characterization of the following phenotypes: developmental delayand alterations in brain and liver morphology. Additionally, according to observations from our group based on a Brazilian cohort of individuals with XGS, a hyperphagic behavior may be a common feature, which prompted us to investigate the hypothesis of satiation and/or metabolic changes in this model.