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
An ASD-associated human mutation of the X-linked TRPC5 gene, deletion of lysine 34 (K34del), was modeled in mouse. Both hemizygous mutant males and heterozygous mutant females show susceptibility to obesity, increased hoarding behavior, increased anxiety and decreased sociability. In heterozygous mutant dams, there is a decrease in maternal nurturing behavior and an increase in postpartum depression-like behavior. Overexpression of TRPC5 in the paraventricular nucleus of the hypothalamus ameliorates the metabolic, anxiety and sociability phenotypes in males and females, and in dams, it ameliorates maternal nurturing and postpartum depression-like behaviors. Hemizygous and heterozygous mice with a conditional knockout allele, where Trpc5 gene is ablated in oxytocin neurons, show similar phenotypes as the K34del mutants. Metabolic phenotypes in these conditional knockouts are rescued with oxytocin treatment in this model.
References
Type
Title
Author, Year
Primary
Loss of transient receptor potential channel 5 causes obesity and postpartum depression
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
CRISPR-Cas9 gene editing was used to generate the knock-in mouse with the deletion of one amino acid residue (K34) in Trpc5 protein which was referred to as Trpc5^K34del. The gene targeting was designed and performed by Genetically Engineered Rodent Models (GERM) Core at BCM. Founder animals were screened for the deletion by PCR amplification of tail DNA. Three independent lines were sequenced for further confirmation of the deletion. One of these lines was crossed to C57BL/6J to produce study cohorts.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Yongxiang Li (Baylor College of Medicine)
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
CRISPR-Cas9 gene editing was used to generate the knock-in mouse with the deletion of one amino acid residue (K34) in Trpc5 protein which was referred to as Trpc5^K34del. The gene targeting was designed and performed by Genetically Engineered Rodent Models (GERM) Core at BCM. Founder animals were screened for the deletion by PCR amplification of tail DNA. Three independent lines were sequenced for further confirmation of the deletion. One of these lines was crossed to C57BL/6J to produce study cohorts.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Yongxiang Li (Baylor College of Medicine)
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
CRISPR-Cas9 gene editing was used to generate the knock-in mouse with the deletion of one amino acid residue (K34) in Trpc5 protein which was referred to as Trpc5^K34del. The gene targeting was designed and performed by Genetically Engineered Rodent Models (GERM) Core at BCM. Founder animals were screened for the deletion by PCR amplification of tail DNA. Three independent lines were sequenced for further confirmation of the deletion. One of these lines was crossed to C57BL/6J to produce study cohorts.
Allele Type: ASD mutation
Strain of Origin: C57BL/6J
Genetic Background: C57BL/6J
ES Cell Line: N/A
Mutant ES Cell Line: Model Source: Yongxiang Li (Baylor College of Medicine)
Model Type:
Genetic
Model Genotype:
Hemizygous
Mutation:
The Cre-loxP approach was used to delete Trpc5 in oxytocin-expressing neurons. Mice carrying the Trpc5^flox allele (not described) were crossed with mice carrying the Oxt-Cre transgene (MGI:5523143), which expresses Cre in the Oxt gene locus.
Allele Type: Conditional knockout
Strain of Origin: 129S6/SvEvTac (Oxt-Cre)
Genetic Background: C57BL/6
ES Cell Line: W4 (Oxt-Cre)
Mutant ES Cell Line: Model Source: Yongxiang Li (Baylor College of Medicine); Jackson
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
The Cre-loxP approach was used to delete Trpc5 in oxytocin-expressing neurons. Mice carrying the Trpc5^flox allele (not described) were crossed with mice carrying the Oxt-Cre transgene (MGI:5523143), which expresses Cre in the Oxt gene locus.
Allele Type: Conditional knockout
Strain of Origin: 129S6/SvEvTac (Oxt-Cre)
Genetic Background: C57BL/6
ES Cell Line: W4 (Oxt-Cre)
Mutant ES Cell Line: Model Source: Yongxiang Li (Baylor College of Medicine); Jackson
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.
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.
Description: Food intake is not significantly different between wildtype and homozygous mice on standard chow diet, but treatment-induced food intake attenuation is present in wildtype mice and missing in hemizygous mice. Treatment consists of chronic injections of benzothiadiazide derivative (Trpc5 activator).
Exp Paradigm: Food intake measurements during chronic intraperitoneal injections of benzothiadiazine derivative (BTD), a Trpc5 activator.
Description: Body weight is not significantly different between wildtype and homozygous mice on standard chow diet, but treatment-induced weight decrease is present in wildtype mice and missing in hemizygous mice. Treatment consists of chronic injections of benzothiadiazide derivative (Trpc5 activator).
Exp Paradigm: Body weight measurements during chronic intraperitoneal injections of benzothiadiazine derivative (BTD), a Trpc5 activator.
Description: Hemizygous conditional knockout mice show a decrease in locomotor activity in the dark phase and total 24-hour day, and no change in the light phase, compared to control mice.
Exp Paradigm: TSE PhenoMaster metabolic cages, high-fat diet
Description: Hemizygous conditional knockout mice showed decreased interaction time with conspecific, and increased interaction time with object, and a decreased preference ratio for social interaction, compared to control mice.
Description: Hemizygous conditional knockout mice exhibited increased food intake compared to control mice on a standard chow diet. Specifically increased food intake was significant in the dark phase and the overall 24-hour period.
Exp Paradigm: Standard chow diet, TSE PhenoMaster metabolic cages
Description: Hemizygous conditional knockout mice exhibited increased fat mass compared to control mice on a standard chow diet, and also an increase in lean mass.
Exp Paradigm: Standard chow diet
Description: Hemizygous conditional knockout mice exhibited increased weight compared to control mice on a standard chow diet.
Exp Paradigm: Standard chow diet
Description: Hemizygous conditional knockout mice show decreased time spent in center, distance travelled in center and number of center entries in the open field test.
Description: Heterozygous conditional knockout mice show a decrease in locomotor activity in the dark phase and total 24-hour day, and no change in the light phase, compared to control mice.
Exp Paradigm: TSE PhenoMaster metabolic cages, high-fat diet
Description: Heterozygous conditional knockout mice exhibited increased food intake compared to control mice on a standard chow diet. Specifically, the increased food intake was significant in the overall 24-hour period, with trends to increase in both light and dark phases of the circadian cycle.
Exp Paradigm: Standard chow diet, TSE PhenoMaster metabolic cages
Description: Heterozygous conditional knockout mice exhibited increased weight compared to control mice on a standard chow diet.
Exp Paradigm: Standard chow diet
Description: Heterozygous conditional knockout mice show decreased time spent in center and number of center entries in the open field test, and a trend for decreased distance travelled in center.
Description: Heterozygous conditional knockout dams displayed significantly reduced maternal care behavior, including decreased crouching, grooming, nest building, and time in nest.
Description: Heterozygous conditional knockout 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.
