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Hundreds of genes are mutated in non-syndromic intellectual disability (ID) and autism spectrum disorder (ASD), with each gene often involved in only a handful of cases. Such heterogeneity can be daunting, but rare recessive loss of function (LOF) mutations can be a good starting point to provide insight into the mechanisms of neurodevelopmental disease. Biallelic LOF mutations in the signaling scaffold  CC2D1A  cause a rare form of autosomal recessive ID, sometimes associated with ASD and seizures. In parallel, we recently reported that  Cc2d1a -deficient mice present with cognitive and social deficits, hyperactivity and anxiety. In Drosophila, loss of the only ortholog of  Cc2d1a, lgd , is embryonically lethal, while in vertebrates,  Cc2d1a  has a homolog  Cc2d1b  which appears to be compensating, indicating that  Cc2d1a  and  Cc2d1b  have a redundant function in humans and mice. Here, we generate an allelic series of  Cc2d1a  and  Cc2d1b  LOF to determine the relative role of these genes during behavioral development. We generated  Cc2d1b  knockout (KO),  Cc2d1a/1b  double heterozygous and double KO mice, then performed behavioral studies to analyze learning and memory, social interactions, anxiety, and hyperactivity. We found that  Cc2d1a  and  Cc2d1b  have partially overlapping roles. Overall, loss of  Cc2d1b  is less severe than loss of  Cc2d1a , only leading to cognitive deficits, while  Cc2d1a/1b  double heterozygous animals are similar to  Cc2d1a -deficient mice. These results will help us better understand the deficits in individuals with  CC2D1A  mutations, suggesting that recessive  CC2D1B  mutations and  trans -heterozygous  CC2D1A  and  CC2D1B  mutations could also contribute to the genetics of ID.

Loss of the Intellectual Disability and Autism Gene Cc2d1a and Its Homolog Cc2d1b Differentially Affect Spatial Memory, Anxiety, and Hyperactivity