BOD1-associated syndromic intellectual disability: from the clinic to a mouse model

Abstract

Consanguinity, common in many Middle Eastern populations, increases the likelihood of homozygosity for rare mutations, leading to autosomal recessive diseases. Our project aimed to identify the pathogenic variant responsible for a syndromic neurodevelopmental disorder (NDD) in a Lebanese family and to study the effects of this mutation on protein expression, development and physiology. We identified a homozygous stop-gain mutation (p.R151*) in the BOD1 gene, published in Clinical Genetics, which was linked to intellectual disability, mild dysmorphic features, and endocrine dysfunction in the proband. To explore the impact of this mutation, we used CRISPR-Cas9 to create a knock-in of the mutation in HEK293T cells. Western blot analysis revealed the production of a truncated, unstable Bod1 protein, indicating that the mutation significantly disrupts protein expression. Additionally, we generated a Bod1 knock-out mouse model to investigate the physiological role of BOD1 in cognitive function and brain development. Behavioral tests on Bod1 KO mice revealed hyperactivity and cognitive deficits, particularly in females, along with reductions in hippocampal and subiculum volumes. These findings suggest that BOD1 plays a critical role in neurodevelopment, impacting both cognitive function and brain structure. This study provides new insights into the molecular mechanisms underlying BOD1-related syndromic intellectual disability and underscores the importance of BOD1 in neurodevelopmental processes.

Date of Award	22 Aug 2024
Original language	English
Awarding Institution	University of Namur
Supervisor	Olivier De Backer (Supervisor), Eliane Chouery (Co-Supervisor), Charles Nicaise (President), Thierry Arnould (Jury), Rene REZSOHAZY (Jury) & Françoise Gofflot (Jury)