Alternative titles; symbols
HGNC Approved Gene Symbol: CACHD1
Cytogenetic location: 1p31.3 Genomic coordinates (GRCh38): 1:64,470,129-64,693,053 (from NCBI)
CACHD1 is a type I membrane protein involved that modulates the activities of voltage-gated Ca(2+) channels (VGCCs) (Cottrell et al., 2018; Dahimene et al., 2018).
By sequencing clones obtained from a size-fractionated human fetal brain cDNA library, Nagase et al. (2000) cloned CACHD1, which they designated KIAA1573. KIAA1573 encodes a predicted protein of 1,185 amino acids. RT-PCR ELISA detected low to moderate KIAA1573 expression in all human tissues examined, with highest expression in adult brain, kidney, and ovary. Among adult brain regions, KIAA1573 expression was high in thalamus and moderate in all other regions.
Cottrell et al. (2018) reported that human CACHD1 contains a predicted exofacial N terminus, a von Willebrand factor (VWF; 613160) A (VWA) domain, 2 bacterial chemosensory-like cache domains, and a short hydrophobic transmembrane domain followed by an intracellular C terminus. CACHD1 shares structural similarities with members of the alpha-2/delta voltage-gated Ca(2+) channel auxiliary subunit family (see CACNA2D1, 114204). RT-PCR analysis showed that CACHD1 was highly expressed in hippocampus and thalamus of rat and human brain. Western blot analysis revealed that CACHD1 was present at the plasma membrane of transfected human embryonic kidney (HEK) cells.
By in situ hybridization, Tian et al. (2021) showed that Cachd1 expression was weak in cochleae of 1-month-old mice. However, Cachd1 expression was apparent in cochlear ducts of embryonic day-14.5 (E14.5) and E16.5 embryos, especially in the thickened epithelium along the floor of the cochlear duct in E14.5 embryos.
By radiation hybrid analysis, Nagase et al. (2000) mapped the CACHD1 gene to chromosome 1.
Cottrell et al. (2018) stated that the CACHD1 gene maps to chromosome 1p13.3.
Tian et al. (2021) stated that the Cachd1 gene maps to mouse chromosome 4.
By heterologous expression in HEK cells, Cottrell et al. (2018) showed that human CACHD1 promoted cell surface expression of CaV3.1 (CACNA1G; 604065) and formed a complex with CaV3.1 at the cell surface. By forming a complex with CaV3 family members, CACHD1 increased the T-type Ca(2+) current by increasing the probability of channel opening at the cell surface. Expression of human CACHD1 increased CaV3-mediated excitability in rat hippocampal neurons, confirming a CACHD1-mediated selective increase in T-type Ca(2+) current.
By immunoprecipitation analysis, Dahimene et al. (2018) showed that rabbit CaV2.2 (CACNA1B; 601012) and rat alpha-2/delta-1 (CACNA2D1) interacted at the cell surface, but that the interaction was disrupted by mutation of aps122 in CaV2.2 to ala (D122A). Rat and zebrafish Cachd1 was also expressed on the cell surface and interacted and colocalized with CaV2.2, though the interaction was weaker compared with that of alpha-2/delta-1. Both alpha-2/delta-1 and Cachd1 could increase CaV2.2 currents, but the D122A mutation in CaV2.2 only prevented the effects alpha-2/delta-1, and not of Cachd1, on Cav2.2 currents. Cachd1 displayed a selectivity for specific calcium channel isoforms, as it did not increase currents through the related rat CaV2.1 (CACNA1A; 601011) channel under the same conditions, whereas alpha-2/delta-1 produced the same effect on both isoforms. The D122A mutation reduced expression of alpha-2/delta-1, but not Cachd1, at the plasma membrane. Both alpha-2/delta-1 and Cachd1 increased trafficking of CaV2.2 into hippocampal neurites, though Cachd1 was less effective than alpha-2/delta-1. However, the D122A mutation abolished or decreased the trafficking effect for both alpha-2/delta-1 and Cachd1. The findings suggested that, unlike alpha-2/delta-1, Cachd1 does not use the D122-containing domain I of CaV2.2 for interaction with CaV2.2. Further analysis revealed that Cachd1 competed with alpha-2/delta-1 for interaction with CaV2.2 and thereby affected the function of alpha-2/delta-1.
Stephens and Cottrell (2019) reviewed the role of CACHD1 in modifying VGCC activity.
Tian et al. (2021) identified a missense mutation in the Cachd1 gene as the cause of the recessive 'tilt-o-whirl' (tow) mouse mutation, which results in vestibular and auditory dysfunction. The authors generated Cachd1 -/- mice and found that they displayed a phenotype similar to that of tow/tow mice, with auditory and vestibular dysfunction and overt circling and head-tilting behaviors. Inner ears of Cachd1 -/- mice showed morphologic and histopathologic deficiencies compared with controls. Moreover, Cachd1 -/- mice had defects in cochlear function and, consistent with the role of Cachd1 in modulating VGCC activity, Ca(2+) concentrations in cochlear endolymph of Cachd1 -/- mice were elevated.
Cottrell, G. S., Soubrane, C. H., Hounshell, J. A., Lin, H., Owenson, V., Rigby, M., Cox, P. J., Barker, B. S., Ottolini, M., Ince, S., Bauer, C. C., Perez-Reyes, E., Patel, M. K., Stevens, E. B., Stephens, G. J. CACHD1 is an alpha-2/delta-like protein that modulates CaV3 voltage-gated calcium channel activity. J. Neurosci. 38: 9186-9201, 2018. [PubMed: 30181139] [Full Text: https://doi.org/10.1523/JNEUROSCI.3572-15.2018]
Dahimene, S., Page, K. M., Kadurin, I., Ferron, L., Ho, D. Y., Powell, G. T., Pratt, W. S., Wilson, S. W., Dolphin, A. C. The alpha-2/delta-like protein Cachd1 increases N-type calcium currents and cell surface expression and competes with alpha-2/delta-1. Cell Rep. 25: 1610-1621, 2018. [PubMed: 30404013] [Full Text: https://doi.org/10.1016/j.celrep.2018.10.033]
Nagase, T., Kikuno, R., Nakayama, M., Hirosawa, M., Ohara, O. Prediction of the coding sequences of unidentified human genes. XVIII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. DNA Res. 7: 273-281, 2000. [PubMed: 10997877] [Full Text: https://doi.org/10.1093/dnares/7.4.271]
Stephens, G. J., Cottrell, G. S. CACHD1: A new activity-modifying protein for voltage-gated calcium channels. Channels (Austin) 13: 120-123, 2019. [PubMed: 30983497] [Full Text: https://doi.org/10.1080/19336950.2019.1600968]
Tian, C., Johnson, K. R., Lett, J. M., Voss, R., Salt, A. N., Hartsock, J. J., Steyger, P. S., Ohlemiller, K. K. CACHD1-deficient mice exhibit hearing and balance deficits associated with a disruption of calcium homeostasis in the inner ear. Hear. Res. 409: 108327, 2021. [PubMed: 34388681] [Full Text: https://doi.org/10.1016/j.heares.2021.108327]