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 constructs 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 hemizygous conditional knockout male 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 total distance travelled or velocity in the open field test.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus did not affect rearing counts in the open field test, but did increase duration of rearing.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus restored social preference in hemizygous mutant mice compared to mutant mice without Trpc5 overexpression. Specifically, overexpression led to increased interaction with conspecific, and an increase in the social preference ratio.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus did not decrease energy expenditure on a high-fat diet, in hemizygous mutant mice compared to mutant mice without Trpc5 overexpression. Overexpression did decrease energy expenditure on standard chow diet.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus did not significantly decrease (p=0.081) the fat mass on a high-fat diet, in hemizygous mutant mice compared to mutant mice without Trpc5 overexpression.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus decreased food intake on a high-fat diet, in hemizygous mutant mice compared to mutant mice without Trpc5 overexpression. The decrease was significant in the dark phase, and the overall 24-hour period.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus decreased the body weight on a high-fat diet, in hemizygous mutant mice compared to mutant mice without Trpc5 overexpression.
Description: Overexpression of Trpc5 in the paraventricular nucleus of the hypothalamus decreased anxiety in hemizygous mutant mice compared to mutant mice without Trpc5 overexpression. Specifically, overexpression led to increased distance in center, time spent in center and center entries in the open field.
Description: Hemizygous 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: Treatment-induced activation of hypothalamic pro-opiomelanocortin neurons (increased c-Fos levels) is present in wildtype mice but missing in hemizygous mice. Treatment includes i.p. injection of benzothiadiazide derivative (Trpc5 activator), leptin or lorcaserin (serotonin 2C receptor agonist). Exp Paradigm: c-Fos levels in Pomc neurons were quantified using immunohistochemistry after intraperitoneal injection of benzothiadiazine derivative (BTD), a Trpc5 activator (10 mg/kg), leptin (5 mg/kg) or lorcaserin (3 mg/kg)
Description: Hemizygous mice showed significantly increased attacks toward the intruder with reduced latency to attack, and increased number and duration of attacks.
Description: Hemizygous mice displayed significantly reduced interaction with another mouse compared to wildtype mice, and a significant decrease in preference ratio.
Description: Hemizygous mice on a high-fat diet exhibited increased fat mass compared to wildtype mice on a high-fat diet, and no change in lean mass. Exp Paradigm: High-fat diet
Description: Hemizygous mice on a high-fat diet exhibited increased hyperphagia compared to wildtype mice on a high-fat diet. Exp Paradigm: High-fat diet
Description: Food intake is not significantly different between wildtype and hemizygous mice on standard chow diet, but treatment-induced food intake attenuation is present in wildtype mice and missing in hemizygous mice. Treatment includes i.p. injection of benzothiadiazide derivative (Trpc5 activator), leptin or lorcaserin (serotonin 2C receptor agonist). Exp Paradigm: Food intake measurements before and after intraperitoneal injection of benzothiadiazine derivative (BTD), a Trpc5 activator (10 mg/kg), leptin (5 mg/kg) or lorcaserin (3 mg/kg)
Description: There was a significant decrease in energy expenditure between hemizygous and wildtype mice on a high-fat diet. Exp Paradigm: TSE PhenoMaster metabolic cages, high-fat diet
Description: Hemizygous mice showed decreased entries to the center, and decreased time and distance in the center, and decreased duration of rearing behavior in the center of the open field, compared to wildtype mice.
Description: Hemizygous mice showed an increase in the amount of food hoarded when housed at 28 C ambient temperature, but no change in behavior at 24 C.
