Deficiency of FRMD5 results in neurodevelopmental dysfunction and autistic-like behavior in mice

Abstract Postsynaptic scaffolding proteins are causally associated with the pathophysiology of autism spectrum disorders (ASDs), a finding that is supported by several large-scale genomic studies 1,2 as well as in vitro and in vivo neurobiological studies of mutations in animal models 3,4. However, since ASD patients illustrate distinct phenotypic and genetic heterogeneity, each individual mutation gene accounts for only a small proportion (<2%) of cases 1,5. Recently, a human genetic study indicated that de novo variants in FERM domain-containing-5 (FRMD5) are related to neurodevelopmental abnormalities 6. Here, we reveal that deficiency of the scaffolding protein FRMD5 results in neurodevelopmental dysfunction and ASD-like behavior in mice. FRMD5 deficiency leads to morphological abnormalities in neurons and synaptic dysfunction in mice. Frmd5-deficient mice exhibited learning and memory dysfunction, impaired social function, and increased repetitive stereotyped behavior. Mechanistically, tandem mass tag (TMT)-labeled quantitative proteomics showed that FRMD5 deletion affected the distribution of synaptic proteins involved in the pathological process of ASD. Taken together, our findings first delineate the critical role of FRMD5 in neurodevelopment and ASD pathophysiology, indicating a therapeutic potential for the treatment of ASD.