CC2D1A – Autosomal Recessive Non-Syndromic Intellectual Disability

CC2D1A encodes Coiled-coil and C2 domain containing 1A (Freud-1), a scaffold protein involved in transcriptional repression and NF-κB activation in neurons. Loss-of-function mutations in CC2D1A disrupt neuronal signaling pathways and underlie a rare form of autosomal recessive non-syndromic intellectual disability ([PMID:16033914]).

Homozygosity mapping in nine consanguineous families identified a recessive genomic deletion, c.1223-294_1642-220del, removing DM14 and C2 domains of CC2D1A in all affected individuals ([PMID:16033914]). All obligate carriers were heterozygous and 192 matched controls lacked this deletion, confirming segregation and rarity.

Functional studies demonstrate that human Freud-1L binds dual repressor elements in the 5-HT1A receptor promoter and represses transcription in neuronal cells ([PMID:17714190]). Additionally, CC2D1A interacts with phosphodiesterase 4D (PDE4D) to fine-tune cAMP-PKA-CREB signaling, and deletion of the fourth DM14 and C2 domains leads to constitutive PDE4D hyperactivity and impaired downstream CREB phosphorylation ([PMID:23826796]).

Neuron-specific conditional knockout of Cc2d1a in mouse forebrain causes deficits in long-term potentiation, object location memory, and dendritic arbor complexity, accompanied by Rac1 hyperactivation; partial pharmacological blockade of Rac1 rescues synaptic and cognitive impairments ([PMID:30992372]).

The concordance of multi-family segregation of biallelic CC2D1A loss-of-function variants with robust in vitro and in vivo functional data supports haploinsufficiency as the pathogenic mechanism. CC2D1A genetic testing is recommended for diagnosis of autosomal recessive non-syndromic intellectual disability and may inform exploration of Rac1-targeted therapies.

References

• Journal of medical genetics • 2006 • The CC2D1A, a member of a new gene family with C2 domains, is involved in autosomal recessive non-syndromic mental retardation. PMID:16033914
• The European journal of neuroscience • 2007 • The mental retardation gene CC2D1A/Freud-1 encodes a long isoform that binds conserved DNA elements to repress gene transcription. PMID:17714190
• Cell communication and signaling • 2013 • Phosphodiesterase activity is regulated by CC2D1A that is implicated in non-syndromic intellectual disability. PMID:23826796
• The Journal of neuroscience • 2019 • Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation. PMID:30992372

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