Diagnostic exome sequencing in 100 patients with severe intellectual disability (ID) and their parents in de Ligt et al., 2012 identified a maternally-inherited missense variant in the TRPC5 gene in a male ID proband who was also diagnosed with autism spectrum disorder (ASD) and Tourette syndrome. Analysis of 54 male patients presenting with intellectual disability (ID) and a family history suggesting X-linked inheritance or maternal skewed X-chromosome inactivation using an X-chromosome-specific microarray in Mignon-Ravix et al., 2014 identified a deletion of the first exon of the TRPC5 gene in a child presenting with ID and autism spectrum disorder (ASD). Leitao et al., 2022 presented four previously unreported individuals with TRPC5 variants: three brothers with ASD and intellectual disability with a maternally-inherited missense variant that was experimentally confirmed to result in a constitutively active current; and a male patient with high-functioning ASD with a maternally-inherited nonsense variant. De novo coding variants in TRPC5 have also been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014), in patients with DD/ID (Deciphering Developmental Disorders Study 2015; Lelieveld et al., 2016), and in a proband with congenital heart disease (Homsy et al., 2015).
Molecular Function
This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1).
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Diagnostic exome sequencing in persons with severe intellectual disability.
Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes
Rescue Type:
RESCUE-Genetic
Rescue Paradigm:
Mice with the Trpc5^K34del mutation were crossed with mice carrying the Oxt-Cre transgene (MGI:5523143). For overexpression of Trpc5 in OXT neurons, stereotactic injections of viral construct AAV-hSyn-DIO-GCaMP6m (control group) or AAV-hSyn-DIO-Trpc5-flag (rescue group) were bilaterally delivered into the paraventricular nucleus of the hypothalamus of adult virgin heterozygous conditional knockout female mice.
Treatment does not improve measured phenotype (was expected to do so)
Ameliorated
Treatment provides partial correction or improvement of measured phenotype
No adverse effect
Treatment does not affect the parameter adversely
Sustained effect
Treatment has long term effect of restoration or amelioration, tested AFTER stopping administration (not applied for continuing long-term treatment) . Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
No sustained effect
Treatment has no long term of restoration or amelioration detectable, after stopping administration. Will be applied only where treatment has had restorative effects during administration or in the first battery of tests conducted.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus did not affect the number of pups born or pup survival in heterozygous mutant dams compared to mutant dams without Trpc5 overexpression.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus increased interest in the rewarding properties of sucrose in a sucrose preference test for heterozygous mutant dams compared to mutant dams without Trpc5 overexpression.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus decreased immobility in the forced swim test for heterozygous mutant dams compared to mutant dams without Trpc5 overexpression.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus increased maternal care behavior in heterozygous mutant dams compared to mutant dams without Trpc5 overexpression. Specifically, overexpression led to an increase in grooming and time in nest, and a trend to increased crouching behavior (p=0.087).
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus increased pup retrieval behavior in heterozygous mutant dams compared to mutant dams without Trpc5 overexpression. Specifically, overexpression led to reduced latency to retrieve pups and increased number of pup retrievals in the home cage pup retrieval test and in the open field pup retrieval test.
Description: Heterozygous male mice showed increased awake time specifically during a fasting period, and no change in sleep during fed periods. Exp Paradigm: TSE PhenoMaster metabolic cages
Description: Heterozygous mice showed reduced locomotor activity compared with wildtype mice at 24 C and 28 C. Exp Paradigm: TSE PhenoMaster metabolic cages, high-fat diet
Description: Heterozygous mice showed a lower respiratory exchange rate than wildtype mice, and unlike wildtype mice heterozygous mice showed no adaptation of the respiratory exchange rate in response to increased temperature. Exp Paradigm: TSE PhenoMaster metabolic cages, high-fat diet
Description: On PPD 12, we also detected severely impaired suckling-induced prolactin release in Trpc5K34del/+ dams, although their baseline prolactin levels (before suckling) were comparable to those of WT dams
Description: On postpartum day 1, significantly more heterozygous dams showed abandon behavior compared with wildtype dams, with their pups found scattered within the bedding material. Heterozygous dams also displayed significantly reduced crouching, grooming, nest building, and time in nest in keeping with a reduced level of maternal care.
Description: Heterozygous dams showed significantly increased latency to retrieve pups and reduced number of pup retrievals in the home cage pup retrieval test and in the open field pup retrieval test. Heterozygous dams also showed a decrease in travel distance and velocity in the open field pup retrieval test.
