CC2D1A Regulates Human Intellectual and Social Function as well as NF-κB Signaling Homeostasis

Abstract

SUMMARY Autism spectrum disorder (ASD) and intellectual disability (ID) are often comorbid, but the extent to which they share common genetic causes remains controversial. Here, we present two autosomal-recessive “founder” mutations in the CC2D1A gene causing fully penetrant cognitive phenotypes, including mild-to-severe ID, ASD, as well as seizures, suggesting shared developmental mechanisms. CC2D1A regulates multiple intracellular signaling pathways, and we found its strongest effect to be on the transcription factor nuclear factor κB (NF-κB). Cc2d1a gain and loss of function both increase activation of NF-κB, revealing a critical role of Cc2d1a in homeostatic control of intra-cellular signaling. Cc2d1a knockdown in neurons reduces dendritic complexity and increases NF-κB activity, and the effects of Cc2d1a depletion can be rescued by inhibiting NF-κB activity. Homeostatic regulation of neuronal signaling pathways provides a mechanism whereby common founder mutations could manifest diverse symptoms in different patients.

Abrogated Freud-1/Cc2d1a Repression of 5-HT1A Autoreceptors Induces Fluoxetine-Resistant Anxiety/Depression-Like Behavior

“…In addition to 5-HT1A and dopamine-D2 gene repression, Freud-1 induces NF-κB expression (Matsuda et al, 2003;Zhao et al, 2010). Gene deletion of Freud-1 reduces NF-κB signaling to synaptic plasticity in cortical development, leading to abnormal cortical dendrite organization and reduced dendritic spine density (Manzini et al, 2014). However, these effects of Freud-1 deletion appear to be developmental, and deletion of Freud-1 in adulthood did not appear to affect neuronal organization (Oaks et al, 2016).…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…Homozygosity mapping was also used to identify novel rare, recessive loci in syndromes including autism symptoms. These include a protein truncating mutation in CC2D1A in 9 consanguineous families with severe autosomal recessive nonsyndromic mental retardation [183][184][185]. CC2D1A is a putative signal transducer involved in positive regulation of the I-κB kinase/nuclear factor-κB cascade.…”

Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID)

“…In the mutant protein, this deletion introduced a frameshift mutation, a nonsense codon at amino acid 438, and also created a 30-amino acid nonsense peptide. The Saudi and Pakistani families with autism spectrum disorder and NS-ID phenotypes were reported by Manzini et al [27] did not carry the Israeli-Arab deletion. Instead, in the Saudi families, a homozygous transversion was identified at the exon-intron junction of exon 6 (c.748+1 G > T) leading to the skipping of exon 6, a frameshift mutation at amino acid 172, and an early stop codon at position amino acid 223 (p. Thr172Valfs*51).…”

“…However, in Pakistani families, a 1 bp deletion in exon 3 (c.346 delA) leading to an early frameshift mutation (p.Lys116Argfs*81) was identified. This loss of function of the CC2D1A protein in neurons results in increased NF-κB activity and reduces dendritic complexity, consequently disrupting learning and memory in individuals [13,27].…”

“…NF-κB is involved in the regulation of neuronal differentiation and intracellular trafficking during brain development. NF-κB signaling is affected by gain or loss of function of CC2D1A in developing neurons, leading either to an increase or decrease of neuronal dendritic complexity, which can lead to deficits in learning and memory [13,27].…”