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Relevance to Autism

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).

Molecular Function

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.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
DIXDC1 contributes to psychiatric susceptibility by regulating dendritic spine and glutamatergic synapse density via GSK3 and Wnt/-catenin signaling.
ASD
SCZ, BPD
Support
Dixdc1 is a critical regulator of DISC1 and embryonic cortical development.
Support
DIXDC1 Phosphorylation and Control of Dendritic Morphology Are Impaired by Rare Genetic Variants.
ASD
Support
Abnormal behavior in mice mutant for the Disc1 binding partner, Dixdc1.

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN852R001 
 missense_variant 
  
 p.Ala87Thr 
 Unknown 
  
  
 GEN852R002 
 missense_variant 
  
 p.Arg154Thr 
 Unknown 
  
  
 GEN852R003 
 missense_variant 
  
 p.Gln169Arg 
 Unknown 
  
  
 GEN852R004 
 missense_variant 
  
 p.Lys188Asn 
 Unknown 
  
  
 GEN852R005 
 missense_variant 
  
 p.Gln218His 
 Unknown 
  
  
 GEN852R006 
 missense_variant 
  
 p.Arg249Gln 
 Unknown 
  
  
 GEN852R007 
 missense_variant 
 c.853C>A 
 p.Pro285Thr 
 Unknown 
  
  
 GEN852R008 
 missense_variant 
 c.1099C>T 
 p.Arg367Trp 
 Unknown 
  
  
 GEN852R009 
 missense_variant 
 c.1202C>T 
 p.Thr401Met 
 Unknown 
  
  
 GEN852R010 
 splice_site_variant 
 G>A 
  
 Unknown 
  
  
 GEN852R011 
 missense_variant 
  
 p.Pro194Leu 
 Unknown 
  
  
 GEN852R012 
 missense_variant 
 c.655A>G 
 p.Ser219Gly 
 Unknown 
  
  
 GEN852R013 
 missense_variant 
 c.8G>C 
 p.Gly3Ala 
 Unknown 
  
  
 GEN852R014 
 missense_variant 
  
 p.Pro12Leu 
 Unknown 
  
  
 GEN852R015 
 missense_variant 
 c.67A>T 
 p.Ile23Phe 
 Unknown 
  
  
 GEN852R016 
 missense_variant 
 c.112G>A 
 p.Ala38Thr 
 Unknown 
  
  
 GEN852R017 
 missense_variant 
 c.328A>G 
 p.Arg110Gly 
 Unknown 
  
  
 GEN852R018 
 missense_variant 
  
 p.Met136Thr 
 Unknown 
  
  
 GEN852R019 
 missense_variant 
 c.422A>C 
 p.Asp141Ala 
 Unknown 
  
  
 GEN852R020 
 missense_variant 
  
 p.Cys149Ser 
 Unknown 
  
  
 GEN852R021 
 missense_variant 
 c.475A>T 
 p.Ile159Leu 
 Unknown 
  
  
 GEN852R022 
 missense_variant 
  
 p.Asp161Glu 
 Unknown 
  
  
 GEN852R023 
 missense_variant 
  
 p.Lys229Thr 
 Unknown 
  
  
 GEN852R024 
 missense_variant 
 c.703C>T 
 p.Arg235Trp 
 Unknown 
  
  
 GEN852R025 
 missense_variant 
  
 p.His260Arg 
 Unknown 
  
  
 GEN852R026 
 missense_variant 
 c.815A>C 
 p.Tyr272Cys 
 Unknown 
  
  
 GEN852R027 
 missense_variant 
 c.893G>T 
 p.Gly298Val 
 Unknown 
  
  
 GEN852R028 
 missense_variant 
 c.901G>A 
 p.Asp301Asn 
 Unknown 
  
  
 GEN852R029 
 stop_gained 
 c.916C>T 
 p.Arg306Ter 
 Unknown 
  
  
 GEN852R030 
 missense_variant 
 c.928C>T 
 p.Arg310Ser 
 Unknown 
  
  
 GEN852R031 
 missense_variant 
  
 p.Arg339Leu 
 Unknown 
  
  
 GEN852R032 
 missense_variant 
 c.1034C>T 
 p.Thr345Met 
 Unknown 
  
  
 GEN852R033 
 missense_variant 
 c.1102G>C 
 p.Glu368Gln 
 Unknown 
  
  
 GEN852R034 
 missense_variant 
 c.1273C>T 
 p.Arg425Trp 
 Unknown 
  
  
 GEN852R035 
 missense_variant 
 c.1327G>A 
 p.Val443Ile 
 Unknown 
  
  
 GEN852R036 
 missense_variant 
 c.37G>A 
 p.Val13Ile 
 Unknown 
  
  
 GEN852R037 
 missense_variant 
 c.50G>C 
 p.Gly17Ala 
 Unknown 
  
  
 GEN852R038 
 missense_variant 
 c.127G>A 
 p.Val43Met 
 Unknown 
  
  
 GEN852R039 
 missense_variant 
  
 p.His147Gln 
 Unknown 
  
  
 GEN852R040 
 stop_gained 
 c.514C>T 
 p.Arg172Ter 
 Unknown 
  
  
 GEN852R041 
 missense_variant 
 c.529G>A 
 p.Val177Ile 
 Unknown 
  
  
 GEN852R042 
 missense_variant 
 c.23G>A 
 p.Gly8Glu 
 Familial 
 Paternal 
  
 GEN852R043 
 missense_variant 
 c.127G>A 
 p.Val43Met 
 Familial 
 Paternal 
  
 GEN852R044 
 missense_variant 
 c.1108A>T 
 p.Ile370Leu 
 Familial 
 Maternal 
  
 GEN852R045 
 missense_variant 
 c.1835C>T 
 p.Thr612Met 
 Familial 
 Paternal 
  

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Duplication
 1
 
11
Duplication
 1
 
11
Deletion-Duplication
 4
 

No Animal Model Data Available

 

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