A de novo mutation in RAB11A is associated with neurodevelopmental disorder accompanied by variable multisystem abnormalities

Huiting Zhang¹Jingtao Zhang¹Xue Ma¹Zhehui Chen²Ying Jin¹Mengqiu Li¹Hui Dong¹Yao Zhang¹Feng Gu³Yanling Yang^1*

• ¹Peking University First Hospital, Beijing, China
• ²Women and Children’s Hospital, School of Medicine, Xiamen University, xiamen, China
• ³Hunan Normal University, Changsha, China

RAB11A, a Rab GTPase, is crucial for intracellular transport and recycling. Recently, RAB11A mutations have been found to be associated with neurodevelopmental disorders in cohorts. At present, there are still no effective treatment methods for NDDs caused by RAB11A deficiency, thus, identifying pathogenic mutations and generating disease models is crucial for advancing our understanding of these conditions. We analyzed the clinical presentation of a 4-year and 4-month-old boy with a de novo RAB11A mutation c.370A>G. To examine the consequences of this mutation during early embryonic development, we disrupted the homologous rab11a gene using CRISPR/Cas9 in zebrafish. The affected boy who exhibited intellectual disability showed phenotypic features including cerebral atrophy, obesity, motor disability and abnormal muscle tone. Protein structure predictions indicated that RAB11A mutation affected protein stability and enzymatic activity. CRISPR/Cas9-mediated rab11a deficiency in zebrafish larvae significantly reduced brain, forebrain, and midbrain size.Our study collectively demonstrated that the RAB11A mutation c.370A>G is associated with neurodevelopmental disorders, characterized by motor deficits and brain anomalies. Additionally, we have successfully developed a zebrafish model to recapitulate these neurodevelopmental disorders associated with RAB11A mutations, offering a valuable genetic resource for further investigation into this disease.