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Relevance to Autism

A de novo balanced translocation [t(3;11)(p21;q22)] disrupting the TRPC6 gene was identified in an 8-year-old male proband presenting with non-syndromic autism; further functional studies using patient-specific iPSC-derived neuronal cells and mouse models demonstrated that TRPC6 reduction or haploinsufficiency resulted in altered neuronal development, morphology, and function (Griesi-Oliveira et al., 2014).

Molecular Function

The protein encoded by this gene forms a receptor-activated calcium channel in the cell membrane. The channel is activated by diacylglycerol and is thought to be under the control of a phosphatidylinositol second messenger system. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2) [MIM:603965].

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.
ASD
Support
Evidence for a supportive role of classical transient receptor potential 6 (TRPC6) in the exploration behavior of mice.
Support
Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.
ASD

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN666R001 
 translocation 
  
  
 De novo 
  
 Simplex 
 GEN666R002 
 initiator_codon_variant 
 c.2T>A 
 p.Met1Lys 
 Familial 
 Maternal 
 Simplex 
 GEN666R003 
 stop_gained 
 c.7C>T 
 p.Gln3Ter 
 Familial 
 Paternal 
 Simplex 
 GEN666R004 
 missense_variant 
 c.139C>G 
 p.Pro47Ala 
 Familial 
 Paternal 
 Simplex 
 GEN666R005 
 missense_variant 
 c.620A>C 
 p.Tyr207Ser 
 Familial 
 Maternal 
 Simplex 
 GEN666R006 
 missense_variant 
 c.1057C>T 
 p.Leu353Phe 
 Familial 
 Paternal 
 Simplex 
 GEN666R007 
 missense_variant 
 c.1316C>G 
 p.Pro439Arg 
 Familial 
 Paternal 
 Simplex 
 GEN666R008 
 missense_variant 
 c.1396G>A 
 p.Glu466Lys 
 Familial 
 Paternal 
 Simplex 
 GEN666R009 
 missense_variant 
 c.1679C>T 
 p.Ala560Val 
 Familial 
 Maternal 
 Simplex 
 GEN666R010 
 missense_variant 
 c.2385C>G 
 p.Phe795Leu 
 Familial 
 Maternal 
 Simplex 
 GEN666R011 
 missense_variant 
 c.2424G>T 
 p.Lys808Asn 
 Familial 
 Maternal 
 Simplex 
 GEN666R012 
 frameshift_variant 
 delT 
  
 Familial 
 Maternal 
 Multiplex 

Common

No Common Variants Available
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
11
Duplication
 1
 
11
Deletion
 1
 
11
Deletion
 1
 
11
Deletion
 1
 
11
Deletion-Duplication
 16
 
11
Duplication
 1
 

Model Summary

Trpc6 null mice have similar social behavior to wild-type mice and also do not display increase in repetitive behavior.

References

Type
Title
Author, Year
Primary
Modeling non-syndromic autism and the impact of TRPC6 disruption in human neurons.

M_TRPC6_1_KD-shRNA

Model Type: Genetic
Model Genotype: Homozygous
Mutation: Adult female C57BL/6 mice were stereotaxically injected with the sh-RNA against the Trpc6 gene product into the hilus of the hippocampus. This was meant to cause gene silencing in the new born neurons of the dentate gyrus.
Allele Type: knock-down
Strain of Origin:
Genetic Background: C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_TRPC6_2_KO_HM

Model Type: Genetic
Model Genotype: Homozygous
Mutation: The targeting vector was designed to replace exon 7 of the mouse Trpc6 gene, using the 129Sv genomic library. Homozygous offspring were obtained from crossing hets.
Allele Type: Targeted(knock-out)
Strain of Origin:
Genetic Background: 1:1 129Sv:C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_TRPC6_3_KO_HT

Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Heterozygous mice were obtained by the germ line transmission of targeted Trpc6 gene from chimeras. Chimeras were obtained by injection of correctly targeted ES cell lines into C57BL/6 blastocysts.
Allele Type: Targeted(knock-out)
Strain of Origin:
Genetic Background: 1:1 129Sv:C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source:

M_TRPC6_1_KD-shRNA

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Dendritic architecture: dendritic tree complexity1
Decreased
Description: Trpc6 knock down neurons, in mice brains, show reduced neuronal dendritic arborization compared to control-sh-RNA injected neurons
Exp Paradigm: Scholl analysis
 Confocal microscopy
 Unreported
Neuronal migration1
Decreased
Description: Trpc6 knock down sh-RNA expressing neurons in mice, show defective neuronal migration in the hippocampus, specifically in the layers of the dentate gyrus whereas the control sh-RNA expressing granule cells are found mostly in the inner layer, the Trpc6 knock down mice are found mostly in the upper granule layer of the dentate gyrus. The neurons are characterized 28 days post infection of the retrovirus containing sh-RNA
Exp Paradigm: Number of cell bodies of new born neurons was calculated in the different (3) layers of the dentate gyrus and the molecular layer of the hippocampus
 Confocal microscopy
 6-8 weeks
Action potential firing1
Decreased
Description: Trpc6 knock down neurons, in mice brains, show reduced firing rates compared to control sh-RNA expressing neurons
 
 Unreported
 Not Reported: Circadian sleep/wake cycle, Communications, Developmental profile, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Repetitive behavior, Seizure, Sensory, Social behavior

M_TRPC6_2_KO_HM

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Size/growth1
 No Change
 
 6-8 weeks
Self grooming: perseveration1
 No Change
 
 6-8 weeks
Inanimate object preference1
 No Change
 
 6-8 weeks
Social interaction1
 No Change
 
 6-8 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory

M_TRPC6_3_KO_HT

Category
Entity
Quantity
Experimental Paradigm
Age at Testing
Size/growth1
 No Change
 
 6-8 weeks
Self grooming: perseveration1
 No Change
 
 6-8 weeks
Inanimate object preference1
 No Change
 
 6-8 weeks
Social interaction1
 No Change
 
 6-8 weeks
 Not Reported: Circadian sleep/wake cycle, Communications, Emotion, Homeostasis, Immune response, Learning & memory, Maternal behavior, Molecular profile, Motor phenotype, Neuroanatomy / Ultrastructure / Cytoarchitecture, Neurophysiology, Seizure, Sensory


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
APP amyloid beta (A4) precursor protein 351 P05067 IP/WB; Co-localization
Wang J , et al. 2015
KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1 16531 Q08460 IP/WB; GST
Kim EY , et al. 2008

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