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.
Identification of ultra-rare disruptive variants in voltage-gated calcium channel-encoding genes in Japanese samples of schizophrenia and autism spectrum disorder
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.
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
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Mice carrying knockout allele with 1 bp deletion, leading to the generation of a stop codon (p.Leu783*).
Allele Type: Knockout
Strain of Origin: Not specified
Genetic Background: Not specified
ES Cell Line: Not specified
Mutant ES Cell Line: Model Source: Not specified
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
A771G mutant mice were generated using CRISPR/Cas9 (MGI:7549317), to model human mutation, A769G, found in an ASD proband.
Allele Type: ASD mutation
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Joerg Striessnig
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
A771G mutant mice were generated using CRISPR/Cas9 (MGI:7549317), to model human mutation, A769G, found in an ASD proband.
Allele Type: ASD mutation
Strain of Origin: C57BL/6N
Genetic Background: C57BL/6N
ES Cell Line: Not applicable
Mutant ES Cell Line: Model Source: Joerg Striessnig
Description: In a home cage screening, behavior is automatically categorized based on video recordings of singly housed mice in cages for a period of 24 hours. I772M heterozygous mice show increased locomotion compared with wildtype mice particularly at the start of the dark period (active period of mice), with decreasing locomotion in the later phase of the dark period. A similar peak in activity was observed after the change to the light phase.
Description: Upon injection of ketamine and xylazine for anesthesia, 10 of 13 heterozygous knockin mice showed abnormal jerking movements and tonic-clonic seizures, while no seizures were observed in 19 wildtype mice with the same anesthesia treatment.
Exp Paradigm: anesthesia with ketamine and xylazine
Description: I772M heterozygous mice again preferred a novel social stimulus (new unknown mouse) over a known social stimulus, whereas no significant preference was seen in wildtype littermates.
Description: In a social proximity test (forced social interaction in a constrained space), I772M heterozygous mice show significantly more nose-to-anogenital contacts, jump escape events, uprighting events, crawl-over events, and crawl under-events when in contact with an unknown mouse, but there was no significant increase in nose tip-to-nose tip contacts or nose-to-head contacts.
Description: Exploration of the novel social stimulus is mostly limited to olfaction, manifesting as sniffing. Counting the number of sniffing events at the new unknown mouse relative to the known mouse revealed a similar pattern with no difference for wildtype but a preference for the novel stimulus in I772M heterozygous mice.
Description: I772M heterozygous mice showed a marked preference for a novel social stimulus over a novel empty object, whereas no preference was seen for wildtype mice.
Description: The pattern of calcium oscillations in the adrenal cortex was largely unaffected, which was measured using variable extracellular concentrations of potassium ion and angiotensin II (Ang II) to model effects of the two main stimuli of aldosterone production. Heterozygous knockin mice showed significantly elevated intracellular calcium levels compared with wildtype across almost all concentrations of Ang II and extracellular potassium.
Exp Paradigm: Fura-2
Description: No knockout mice were found from 147 mice at weaning from heterozygous backcrossing (25% homozygous offspring expected). At E8.5, one embryo out of 9 genotyped embryos was a homozygous knockout mouse.
Genotypic ratio of progeny from heterozygous parents
Description: Baseline activity was reduced during the first half of the dark phase in homozygous mutants, while it did not differ among genotypes during the light phase.
Description: Both the total distance traveled (2.3-fold) as well as the average velocity (1.5-fold) were significantly higher in homozygous mutant mice, which also spent significantly less time immobile (decreased by 70%).
Description: Quantification of rearing behavior in a novel environment revealed similar time spent in rearing, whereas the ratio of time over frequency was significantly reduced in homozygous mutant mice.
Description: Quantification of grooming behavior in a novel environment revealed similar time spent in grooming, whereas the ratio of time over frequency was significantly reduced in homozygous mutant mice.
Description: Quantification of direct nose-to-grid interaction time in each chamber revealed homozygous animals did not discriminate between the two grids.
Description: Wildtype mice displayed the expected preference to spend more time in the social chamber compared with the nonsocial one. Conversely, homozygous mice spent more time in the nonsocial chamber.
Description: Mutant mice show reduced body weight that was already evident at birth. Weight gain in male and female mice was monitored weekly starting after weaning (4 weeks). At early developmental stages (4 weeks), heterozygous mutants weighed significantly less. At adulthood (11 weeks), the body weight of heterozygous mice had caught up. The reduced body weight was not associated with changes of other morphometric parameters such as body length.
Genotypic ratio of progeny from heterozygous parents
Description: Mutant mice show reduced body weight that was already evident at birth. Weight gain in male and female mice was monitored weekly starting after weaning (4 weeks). At early developmental stages (4 weeks), Homozygous mutants weighed significantly less (a more pronounced difference than heterozygous mutants). Homozygous mutants consistently weighed less, even at 1 year of age. The reduced body weight was not associated with changes of other morphometric parameters such as body length.
Description: In the light-dark box, where a higher light intensity was used (400 lux compared with 100â??150 lux in the other tests), homozygous mutant mice spent significantly less time in the lit compartment (decreased by 70%).
Description: Quantification of rearing behavior in a novel environment revealed similar time spent in rearing, whereas the ratio of time over frequency was significantly reduced in heterozygous mutant mice.
Description: Both the total distance traveled (1.7-fold) as well as the average velocity (1.2-fold) were significantly higher in heterozygous mutant mice, which also spent significantly less time immobile (decreased by 50%).
Description: DMS-projecting mSN DA neurons displayed a significantly larger sag component (WT 13.3 mV versus HET 16.0 mV, P = 0.0395, unpaired Studentâ??s t test) associated with shorter rebound delay
Description: Neither the time to action potential peak at the rheobase, cell capacitance, nor the action potential shape were affected in mutant slices.
Description: Plotting the injected current versus the elicited number of action potential spikes (input-output curve) revealed a pronounced hyperexcitability of heterozygous medial spiny neurons.
Description: The nigrostriatal pathway consist of dopamine neurons in the substantia nigra project either to the dorsal striatum. In ex vivo brain slices and in the absence of synaptic inputs, dopamine neurons showed spontaneous pacemaker firing. Brain slices from heterozygote animals, dopamine neuron populations (medial and lateral) fired with similar mean frequencies. Medial-projecting dopamine neurons expressing mutant Cav1.3 channels displayed a projection-selective gain-of-function phenotype with elevated baseline firing, while the pacemaker rate of lateral-projecting dopamine neurons was not altered by the presence of mutant channels.
Description: Wildtype mice displayed the expected preference to spend more time in the social chamber compared with the nonsocial one. Conversely, no significant preference was found for heterozygous mutants.
Description: Mutant mice show reduced body weight that was already evident at birth. Weight gain in male and female mice was monitored weekly starting after weaning (4 weeks). At early developmental stages (4 weeks), heterozygous mutants weighed significantly less. At adulthood (11 weeks), the body weight of heterozygous mice had caught up. The reduced body weight was not associated with changes of other morphometric parameters such as body length.
Description: In the light-dark box, where a higher light intensity was used (400 lux compared with 100â??150 lux in the other tests), heterozygous mutant mice spent significantly less time in the lit compartment (decreased by 50%).
