HELP     Sign In
Search

Relevance to Autism

Rare de novo missnese variants in the CACNA1D gene have been identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2012; Iossifov et al., 2012).

Molecular Function

The encoded protein has low voltage-gated calcium channel activity. Mutations in this gene are responsible for primary aldosteronism with seizures and neurologic abnormalities (PASNA; OMIM 615474).

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Calcium channel activation and self-biting in mice.
Self-biting
Positive Association
Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.
SCZ
Support
The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing
ASD
Support
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.
ASD
Support
ASD, ID
BPD, MDD
Support
Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.
ASD
Support
Identification of De Novo JAK2 and MAPK7 Mutations Related to Autism Spectrum Disorder Using Whole-Exome Sequencing in a Chinese Child and Adolesce...
ASD
Support
Exome sequencing of ion channel genes reveals complex profiles confounding personal risk assessment in epilepsy.
Epilepsy
Support
New gain-of-function mutation shows CACNA1D as recurrently mutated gene in autism spectrum disorders and epilepsy.
ASD, ID, epilepsy/seizures
Support
Autism-associated missense genetic variants impact locomotion and neurodevelopment in Caenorhabditis elegans.
ASD
Support
Association of CaV1.3 L-type calcium channels with Shank.
Support
Integrating de novo and inherited variants in 42
ASD
Support
An autism-associated mutation in CaV1.3 channels has opposing effects on voltage- and Ca(2)-dependent regulation.
Support
Genomic insights from a deeply phenotyped highly consanguineous neurodevelopmental disorders cohort
DD, epilepsy/seizures
Support
The Clinical and Genetic Features of Co-occurring Epilepsy and Autism Spectrum Disorder in Chinese Children.
ASD, epilepsy/seizures
Support
Contribution of CACNA1H Variants in Autism Spectrum Disorder Susceptibility
ASD
Support
Large-scale discovery of novel genetic causes of developmental disorders.
Unknown diagnosis
Support
Pathogenicity of de novo CACNA1D Ca2+ channel variants predicted from sequence co-variation
ASD
Support
Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels.
Support
Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder
ASD, SCZ
Support
Somatic and germline CACNA1D calcium channel mutations in aldosterone-producing adenomas and primary aldosteronism.
Support
NGS Custom Panel Implementation in Patients with Non-Syndromic Autism Spectrum Disorders in the Clinical Routine of a Tertiary Hospital
ASD
Support
Diagnostic exome sequencing of syndromic epilepsy patients in clinical practice.
Epilepsy/seizures
Support
Deletion of the voltage-gated calcium channel, Ca V 1.3, causes deficits in motor performance and associative learning
Support
De novo gene disruptions in children on the autistic spectrum.
ASD
Support
Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities
Primary aldosteronism with seizures and neurologic
Support
Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.
ASD
Highly Cited
alpha 1D (Cav1.3) subunits can form l-type Ca2 channels activating at negative voltages.
Recent Recommendation
Functional roles of Cav1.3(alpha1D) calcium channels in atria: insights gained from gene-targeted null mutant mice.
Recent Recommendation
The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice
ASD
Recent Recommendation
CACNA1D de novo mutations in autism spectrum disorders activate Cav1.3 L-type calcium channels.
Recent Recommendation
Synaptic, transcriptional and chromatin genes disrupted in autism.
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN032R001 
 missense_variant 
 c.2306C>G 
 p.Ala769Gly 
 De novo 
  
 Simplex 
 GEN032R002 
 missense_variant 
 c.1219G>A 
 p.Gly407Arg 
 De novo 
  
 Simplex 
 GEN032R003 
 synonymous_variant 
 c.1023C>T 
 p.Asn341= 
 Unknown 
  
 Unknown 
 GEN032R004 
 synonymous_variant 
 c.2802C>T 
 p.Phe934= 
 Unknown 
  
 Unknown 
 GEN032R005 
 missense_variant 
 c.1615G>C 
 p.Ala539Pro 
 Unknown 
  
 Unknown 
 GEN032R006 
 missense_variant 
 c.3952C>T 
 p.Pro1318Ser 
 Unknown 
  
 Unknown 
 GEN032R007 
 missense_variant 
 c.5381T>A 
 p.Ile1794Asn 
 Unknown 
  
 Unknown 
 GEN032R008 
 intron_variant 
 c.4262+560C>T 
  
 Unknown 
  
 Unknown 
 GEN032R009 
 stop_gained 
 c.4897C>T 
 p.Gln1633Ter 
 Unknown 
  
 Unknown 
 GEN032R010 
 splice_site_variant 
 G>T 
  
 Unknown 
  
 Unknown 
 GEN032R011 
 missense_variant 
 c.1810G>A 
 p.Val604Ile 
 De novo 
  
 Simplex 
 GEN032R012 
 missense_variant 
 c.1261G>A 
 p.Asp421Asn 
 Familial 
 Paternal 
 Simplex 
 GEN032R013 
 missense_variant 
 c.1792G>A 
 p.Gly598Ser 
 Familial 
 Paternal 
 Simplex 
 GEN032R014 
 missense_variant 
 c.2789G>A 
 p.Arg930His 
 Familial 
 Paternal 
 Simplex 
 GEN032R015 
 missense_variant 
 c.5816G>A 
 p.Arg1939Gln 
 Familial 
 Paternal 
 Simplex 
 GEN032R016 
 missense_variant 
 c.6053C>A 
 p.Thr2018Asn 
 Familial 
 Maternal 
 Simplex 
 GEN032R017 
 missense_variant 
 c.2612T>G 
 p.Leu871Trp 
 Familial 
 Paternal 
 Simplex 
 GEN032R018 
 missense_variant 
 c.2612T>G 
 p.Leu871Trp 
 Familial 
 Maternal 
 Simplex 
 GEN032R019 
 missense_variant 
 c.3433C>G 
 p.Arg1145Gly 
 Familial 
 Paternal 
 Simplex 
 GEN032R020 
 missense_variant 
 c.3607C>T 
 p.Arg1203Cys 
 Familial 
 Paternal 
 Simplex 
 GEN032R021 
 missense_variant 
 c.176C>T 
 p.Ala59Val 
 Unknown 
  
 Unknown 
 GEN032R022 
 missense_variant 
 c.1033A>C 
 p.Thr345Pro 
 Unknown 
  
 Unknown 
 GEN032R023 
 missense_variant 
 c.2612T>G 
 p.Leu871Trp 
 Unknown 
  
 Unknown 
 GEN032R024 
 missense_variant 
 c.2789G>A 
 p.Arg930His 
 Unknown 
  
 Unknown 
 GEN032R025 
 missense_variant 
 c.3578G>A 
 p.Arg1193His 
 Unknown 
  
 Unknown 
 GEN032R026 
 missense_variant 
 c.5990C>G 
 p.Ser1997Trp 
 Unknown 
  
 Unknown 
 GEN032R027 
 missense_variant 
 c.6053C>A 
 p.Thr2018Asn 
 Unknown 
  
 Unknown 
 GEN032R028 
 missense_variant 
 c.6122G>A 
 p.Arg2041His 
 Unknown 
  
 Unknown 
 GEN032R029 
 missense_variant 
 c.826C>T 
 p.Leu276Phe 
 Unknown 
  
 Unknown 
 GEN032R030 
 missense_variant 
 c.1112A>C 
 p.Tyr371Ser 
 Unknown 
  
 Unknown 
 GEN032R031 
 missense_variant 
 c.1810G>A 
 p.Val604Ile 
 Unknown 
  
 Unknown 
 GEN032R032 
 missense_variant 
 c.3788T>C 
 p.Val1263Ala 
 Unknown 
  
 Unknown 
 GEN032R033 
 missense_variant 
 c.5023C>T 
 p.Arg1675Trp 
 Unknown 
  
 Unknown 
 GEN032R034 
 missense_variant 
 c.1105G>A 
 p.Val369Met 
 Unknown 
  
 Unknown 
 GEN032R035 
 missense_variant 
 c.6275G>A 
 p.Gly2092Glu 
 Unknown 
  
 Unknown 
 GEN032R036 
 missense_variant 
 c.2015C>T 
 p.Ser672Leu 
 De novo 
  
 Unknown 
 GEN032R037 
 missense_variant 
 c.1201G>C 
 p.Val401Leu 
 De novo 
  
  
 GEN032R038 
 missense_variant 
 c.1534T>G 
 p.Trp512Gly 
 De novo 
  
  
 GEN032R039 
 missense_variant 
 c.2206A>G 
 p.Met736Val 
 Familial 
  
 Simplex 
 GEN032R040 
 missense_variant 
 c.3187C>T 
 p.Arg1063Cys 
 Familial 
  
 Simplex 
 GEN032R041 
 missense_variant 
 c.3862G>A 
 p.Ala1288Thr 
 Familial 
  
 Simplex 
 GEN032R042 
 missense_variant 
 c.5846G>A 
 p.Arg1949His 
 Familial 
  
 Simplex 
 GEN032R043 
 missense_variant 
 c.790A>G 
 p.Ile264Val 
 Familial 
  
 Simplex 
 GEN032R044 
 missense_variant 
 c.920A>C 
 p.Asp307Ala 
 Familial 
  
 Simplex 
 GEN032R045 
 missense_variant 
 c.1493G>T 
 p.Arg498Leu 
 Unknown 
  
  
 GEN032R046 
 missense_variant 
 c.4444G>C 
 p.Val1482Leu 
 De novo 
  
  
 GEN032R047 
 missense_variant 
 c.4232C>T 
 p.Thr1411Met 
 De novo 
  
 Simplex 
 GEN032R048 
 missense_variant 
 ENSG00000157388:ENST00000422281:exon21:c.A2771G:p.Y924C,ENSG00000157388:ENST00000288139:exon22:c.A28 
  
 De novo 
  
  
 GEN032R049 
 stop_gained 
 c.4413T>A 
 p.Cys1471Ter 
 Unknown 
  
  
 GEN032R050 
 inframe_deletion 
 c.5017_5019del 
 p.Glu1673del 
 Unknown 
  
  
 GEN032R051 
 inframe_deletion 
 c.5017_5019del 
 p.Glu1673del 
 Unknown 
  
  
 GEN032R052 
 missense_variant 
 c.988G>C 
 p.Gly330Arg 
 Unknown 
  
  
 GEN032R053 
 missense_variant 
 c.2206A>G 
 p.Met736Val 
 Unknown 
  
  
 GEN032R054 
 missense_variant 
 c.2242G>A 
 p.Val748Ile 
 Unknown 
  
  
 GEN032R055 
 missense_variant 
 c.2242G>A 
 p.Val748Ile 
 Unknown 
  
  
 GEN032R056 
 missense_variant 
 G>A 
 p.Gly1438Glu 
 Familial 
 Paternal 
  
 GEN032R057 
 missense_variant 
 c.3039G>T 
 p.Arg1013Ser 
 De novo 
  
 Multiplex 
 GEN032R058 
 missense_variant 
 c.2015C>T 
 p.Ser672Leu 
 De novo 
  
  
 GEN032R059 
 missense_variant 
 c.2513A>G 
 p.Tyr838Cys 
 De novo 
  
  
 GEN032R060 
 missense_variant 
 c.3245A>G 
 p.Tyr1082Cys 
 De novo 
  
  
 GEN032R061 
 missense_variant 
 c.3506G>T 
 p.Gly1169Val 
 De novo 
  
  
 GEN032R062 
 missense_variant 
 c.4724G>C 
 p.Arg1575Pro 
 De novo 
  
  
 GEN032R063 
 synonymous_variant 
 c.6033G>A 
 p.Arg2011%3D 
 De novo 
  
  
 GEN032R064 
 missense_variant 
 c.2140G>T 
 p.Ala714Ser 
 De novo 
  
  
 GEN032R065 
 missense_variant 
 c.2015C>T 
 p.Ser672Leu 
 De novo 
  
  
 GEN032R066 
 missense_variant 
 c.2015C>T 
 p.Ser672Leu 
 Familial 
 Paternal 
 Multiplex 
 GEN032R067 
 missense_variant 
 c.4967G>A 
 p.Arg1656His 
 Unknown 
  
  
 GEN032R068 
 missense_variant 
 c.1825C>T 
 p.Arg609Trp 
 Unknown 
  
  
 GEN032R069 
 missense_variant 
 c.5995C>T 
 p.Arg1999Trp 
 Unknown 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
3
Deletion
 8
 
3
Deletion
 2
 
3
Deletion
 2
 
3
Deletion
 2
 

Model Summary

Cacna1d encodes for Cav1.3, an L-type calcium channel expressed primarily in the adrenal glands. Human mutations that affect the channel properties are modeled in mouse. One mutation I770M is associated with primary aldosteronism, seizures, and neurologic abnormalities (PASNA), the other mutation A769G is a de novo mutation found in an individual with ASD. These mutations are considered gain-of-function mutations and result an increase in aldosterone, a decrease in body weight, social behavior and motor phenotypes. Isradipine is a calcium channel blocker that has a partially ameliorates some motor phenotypes, and aldosterone levels.

References

Type
Title
Author, Year
Primary
Isradipine therapy in Cacna1dIle772Met/+ mice ameliorates primary aldosteronism and neurologic abnormalities
Additional
The human channel gating-modifying A749G CACNA1D (Cav1.3) variant induces a neurodevelopmental syndrome-like phenotype in mice
Model Type: Genetic
Model Genotype: Heterozygous
Mutation: CRISPR/Cas9-mediated mutagenesis in the Cacna1d gene was performed in mice (I772M) to model human mutation I770M, a gain-of-function CACNA1D mutation that causes a rare syndrome of primary aldosteronism, seizures, and neurologic abnormalities (PASNA). Mice were bred using in vitro fertilization, using C57BL/6J females as egg donors and sperm from heterozygous male Cacna1d^I772M/+ mice.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: Not applicable
Mutant ES Cell Line:
Model Source: Ute I. Scholl
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Locomotor activity in diurnal cycle1
Increased
 Home cage behavior
 13-18 weeks
Grip strength1
Decreased
 Neurological exam battery
 13-18 weeks
Tremor1
Increased
 Neurological exam battery
 13-18 weeks
Grip strength1
Decreased
 Home cage behavior
 13-18 weeks
Motor strength and endurance1
Decreased
 General observations
 unreported
General locomotor activity: ambulatory activity1
Increased
 Open field test
 13-18 weeks
Motor coordination and balance1
Decreased
 Accelerating rotarod test
 13-18 weeks
Seizures1
Increased
 Observation of chemically induced seizures
 13-18 weeks
Social approach1
Increased
 Three-chamber social approach test
 13-18 weeks
Social memory1
Increased
 Three-chamber social approach test
 13-18 weeks
Nest building behavior1
Decreased
 Nest building assay
 13-18 weeks
Social interaction1
Increased
 Reciprocal social interaction test
 13-18 weeks
Social interaction1
Increased
 Three-chamber social approach test
 13-18 weeks
Hormone levels1
Increased
 ELISA
 13-18 weeks
Size/growth1
Decreased
 Body length measurement
 13-18 weeks
Mortality/lethality: life span: incomplete penetrance1
Increased
 Survival analysis
 P21-P100
Tissue weight1
Decreased
 Measurement of tissue weight
 13-18 weeks
Size/growth1
Decreased
 Body weight measurement
 13-18 weeks
Maternal nurturing1
Decreased
 General observations
 unreported
Calcium ion uptake1
Increased
 Calcium imaging
 13-18 weeks
Adrenal cortex morphology1
 No change
 Histology
 13-18 weeks
Adrenal cortex morphology1
 No change
 In situ hybridization (ISH)
 13-18 weeks
Mortality/lethality: perinatal1
 No change
 General observations
 unreported
Tissue weight1
 No change
 Measurement of tissue weight
 13-18 weeks
Anxiety1
 No change
 Open field test
 13-18 weeks
Object recognition memory1
 No change
 Novel object recognition test
 13-18 weeks
Gene expression1
 No change
 Quantitative PCR (qRT-PCR)
 13-18 weeks
Brain morphology1
 No change
 Histology
 13-18 weeks
Brain size1
 No change
 Measurement of tissue weight
 13-18 weeks
Neuronal number1
 No change
 Histology
 13-18 weeks
Neuronal number: dopaminergic1
 No change
 In situ hybridization (ISH)
 13-18 weeks
Neuronal size1
 No change
 Histology
 13-18 weeks
Bioactive compound levels1
 No change
 ELISA
 13-18 weeks
Glucose levels1
 No change
 Measurement of blood glucose
 13-18 weeks
Hormone levels1
 No change
 ELISA
 13-18 weeks
Renal function1
 No change
 Urine/blood electrolyte analysis
 13-18 weeks
Seizures1
 No change
 Observation of seizures
 13-18 weeks
Olfaction1
 No change
 Buried food test
 13-18 weeks
Startle response: acoustic stimulus1
 No change
 Startle response test
 13-18 weeks
 Not Reported:

No PIN Data Available
HELP
Copyright © 2017 MindSpec, Inc.