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-Pharmaceutical
Rescue Paradigm:
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. For the acute oxytocin injection study, 20 week old female mice with or without deletion of Trpc5 in OXT neurons were fasted. Then, initial body weight was measured followed by i.p. injections of saline and oxytocin (2 mg/kg). After 30 minutes, food was provided to the cages at and food intake was measured.
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: 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.
