Exome sequence analysis of the DIXDC1 gene in 5977 ASD cases and 7734 controls identified a greater burden of rare sequencing-disrupting SNVs (nonsense, missense, conserved splice-site disrupting) in both DIXDC1 isoforms in cases compared to controls [isoform 1: 68/5977 cases (1.14%) vs. 64/7734 controls (0.83%), p=0.033; isoform 2: 53/5977 cases (8.9%) vs. 41/7734 controls (0.53%), p=0.006] (Martin et al., 2016). A greater burden of rare sequencing-disrupting variants in DIXDC1 was also observed for isoform 1 in bipolar disorder cases (p=0.013) and for isoform 2 in schizophrenia cases (p=0.015). Rare DIXDC1 missense variants observed in ASD cases from the discovery (AASC) cohort failed to rescue deficits in spine density and glutamatergic synapse density in DIXDC1 knockout neurons, with a subset of DIXDC1 missense variants exhibiting hyperactivity in Wnt/beta-catenin signaling activity and dominant-negative effects on spine density and glutamatergic synapse density in wild-type neurons. However, the high frequency of sequence-disrupting DIXDC1 variants in controls (0.53-0.83%, depending on the isoform), the lack of information regarding the mode of inheritance and segregation of variants in ASD cases, and the presence of functionally-relevant ASD missense variants in controls confounds the genetic evidence linking this gene to ASD. Dixdc1 knockout mice display decreased spontaneous locomotor activity, abnormal behavior in the elevated plus maze and deficits in startle reactivity (in Kivime et al., 2011) and abnormal measures of anxiety, depression, and social behavior (in Martin et al., 2016).
The protein encoded by this gene is a positive regulator of the Wnt signaling pathway and is found associated with gamma tubulin at the centrosome.
Type of Disorder
DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/-catenin signaling.