Alternative titles; symbols
HGNC Approved Gene Symbol: ACTRT1
Cytogenetic location: Xq25 Genomic coordinates (GRCh38) : X:128,050,962-128,052,403 (from NCBI)
The ACTRT1 gene encodes a member of the actin-related protein family (summary by Zhang et al., 2022).
Heid et al. (2002) purified bovine Arpt1 from the calyx fraction of epididymal sperm heads. Using peptide sequences to search genomic and EST databases, they identified human ARPT1. The deduced 376-amino acid protein shares 49.3% amino acid identity with beta-actin (ACTB; 102630) and 75.5% identity with ARPT2 (608535). Both ARPT1 and ARPT2 contain several cysteine residues not found in beta-actin or other ARPs. Bovine Arpt1 showed an apparent molecular mass of about 40 kD.
By immunohistochemistry, RT-PCR, and Western blot analysis, Bal et al. (2017) detected expression of ARPT1 in the basal, spinous, and granular layers of the epidermis, but not in dermal connective tissue. High expression was also observed in hair follicles, sebaceous glands, and eccrine sweat glands, with the highest expression in semen samples. Using ultrathin sections of normal epidermis processed for transmission electron microscopy, the authors detected ARPT1 in both the nucleus and cytoplasm of fractionated keratinocytes.
Park et al. (2021) observed ARPT1 expression in differentiated human keratinocytes and epithelial cells.
By Western blot analyses of proteins from subcellular fractions of transfected HEK293T cells or control primary keratinocytes, Bal et al. (2017) observed that ARPT1 was mostly located in the nucleus and was bound to chromatin following stimulation of the Hedgehog (600725) pathway. Transactivation assays in the HaCaT keratinocyte cell line showed that expression of ARPT1 inhibited the Hedgehog pathway. In addition, expression of ARPT1 in primary keratinocytes inhibited GLI1 (165220) expression after stimulation with the Smo (601500) agonist purmophamine. The authors suggested that ARPT1 has a role in regulating the activity of the Hedgehog signaling pathway by exerting negative control over GLI1 expression. Exogenous expression of ACTRT1 reduced in vitro and in vivo proliferation rates of cell lines with aberrant activation of the Hedgehog signaling pathway, indicating a tumor suppressor role for ACTRT1.
Park et al. (2021) reported that the ARPT1 interactome includes proteins involved in ciliogenesis, endosomal recycling, and septin ring formation. They observed that ARPT1 localizes to the ciliary midbody during cytokinesis and to the basal body of primary cilia in interphase, and that ACTRT1-deficient cells showed shortened primary cilia. The authors concluded that ARPT1 supports intact cilia and controls proper ciliogenesis. They showed that ARPT1 is highly expressed during epidermal differentiation, is stabilized by protein kinase C (see 176960), and that ACTRT1 expression is regulated by PKC-delta (176977) and by a noncanonical Hedgehog pathway.
In HEK293T cells, Zhang et al. (2022) found that ACTRT1 immunoprecipitated with the inner acrosomal membrane protein SPACA1 (612739) as well as the nuclear envelope proteins PARP11 (616706) and SPATA46 (617257). Lack of ACTRT1 was shown to weaken the connection between ACTL7A (604303) and SPACA1, an interaction known to anchor the acrosome to the acroplaxome. The authors suggested that ACTRT1, within the sperm perinuclear theca-specific actin-related protein complex (ACTRT1-ACTRT2 608535-ACTL7A-ACTL9 619251), anchors developing acrosomes to the nucleus by connecting with SPACA1, PARP11, and SPATA46.
Heid et al. (2002) stated that the ACTRT1 gene maps to chromosome Xq25.
Bal et al. (2017) found variation in and around the ACTRT1 gene in patients with Bazex-Dupre-Christol syndrome (BDCS; 301845), a disorder characterized by congenital hypotrichosis, follicular atrophoderma, and the development of basal cell neoplasms. They observed that mutant ACTRT1, including a 1-bp duplication present in 2 families, only partially inhibited cell proliferation compared to wildtype; and in tumor xenografts in mice, wildtype but not mutant ACTRT1 attenuated tumor development. Park et al. (2021) studied tissue samples from the BSX patients reported by Bal et al. (2017) and noted shortened ciliary length that correlated with ARTP1 levels; this was confirmed by ACTRT1 knockdown in cultured cells. However, Liu et al. (2022) identified small intergenic duplications at chromosome Xq26.1 in patients with Bazex syndrome who did not have variants in ACTRT1. They modeled maximum tolerated allele counts for the 1-bp duplication reported by Bal et al. (2017) and found that the observed minor allele frequency in population control data was approximately 10,000 times higher than expected, and also noted that other putative loss-of-function variants had been reported in ACTRT1 in both male and female individuals without BDCS. Liu et al. (2022) showed that ACTRT1 was absent from the disease-relevant portions of control hair follicles (stem cell bulge region), and concluded that ACTRT1 variants were unlikely to cause BZX.
Associations Pending Confirmation
From a cohort of 34 infertile Chinese men with acephalic spermatozoa (see spermatogenic failure, 258150), Sha et al. (2021) analyzed whole-exome sequencing data and identified 2 unrelated Han Chinese men with hemizygous missense variants in the ACTRT1 gene: patient F018 had an R32H substitution, and F034 had a Y221C substitution. In each family, the mother was heterozygous for the variant and the father harbored the wildtype allele. Both variants occurred at highly conserved residues and neither was found in the gnomAD database. Most patient sperm were headless, but an occasional head without a tail was observed. Immunofluorescence staining for ACTRT1 showed high expression in the pericentriolar matrix of control sperm, but staining was dislocated and diffuse in patient sperm. With artificial insemination of optimized sperm, both patients and their partners experienced successful pregnancies and childbirth. Noting that a defective head-tail coupling apparatus (HTCA) is the underlying cause of acephalic sperm, Zhang et al. (2022) stated that there was no evidence to indicate that ACTRT1 regulates the HTCA structure. In addition, since the consequences of single-point mutations on ACTRT1 function had not been demonstrated, they suggested that there was not enough evidence to indicate that ACTRT1 is an acephalic spermatozoa-associated gene.
Using CRISPR/Cas9, Sha et al. (2021) generated Actrt1-knockout mice and observed that approximately 60% of sperm were headless. Ultrastructural analysis revealed significant defects of the head-tail coupling apparatus, and the fertility of male mice was severely impaired.
Using CRISPR/Cas9, Zhang et al. (2022) generated an Actrt1-knockout mouse model and observed that, despite normal sperm counts and motility, knockout male mice were severely subfertile compared to wildtype males. Elongated spermatids and sperm from the mutant mice showed deformed heads, and the sperm showed abnormal nuclear morphology. In addition, a disturbance of the typical crescent moon shape of the acrosome was observed in Actrt1-knockout mice. The proportion of acrosomes that were detached from the nucleus was significantly higher in mutant than in wildtype sperm by PNA-FITC staining, and this was confirmed by transmission electron microscopy. The distribution of the acroplaxome was disturbed and was sometimes broken away from the nucleus. The manchette of knockout spermatids was also largely disorganized, which the authors suggested might be a secondary effect of the acrosomal anomalies. The authors also noted that their Actrt1-knockout mice did not exhibit the headless phenotype that was observed by Sha et al. (2021) in their Actrt1-knockout mice, despite similar deletion strategies used in both models.
Bal, E., Park, H.-S., Belaid-Choucair, Z., Kayserili, H., Naville, M., Madrange, M., Chiticariu, E., Hadj-Rabia, S., Cagnard, N., Kuonen, F., Bachmann, D., Huber, M., and 25 others. Mutations in ACTRT1 and its enhancer RNA elements lead to aberrant activation of Hedgehog signaling in inherited and sporadic basal cell carcinomas. Nature Med. 23: 1226-1233, 2017. [PubMed: 28869610] [Full Text: https://doi.org/10.1038/nm.4368]
Heid, H. W., Figge, U., Winter, S., Kuhn, C., Zimbelmann, R., Franke, W. W. Novel actin-related proteins Arp-T1 and Arp-T2 as components of the cytoskeletal calyx of the mammalian sperm head. Exp. Cell Res. 279: 177-187, 2002. [PubMed: 12243744] [Full Text: https://doi.org/10.1006/excr.2002.5603]
Liu, Y., Banka, S., Huang, Y., Hardman-Smart, J., Pye, D., Torrelo, A., Beaman, G. M., Kazanietz, M. G., Baker, M. J., Ferrazzano, C., Shi, C., Orozco, G., and 20 others. Germline intergenic duplications at Xq26.1 underlie Bazex-Dupre-Christol basal cell carcinoma susceptibility syndrome. Brit. J. Derm. 187: 948-961, 2022. [PubMed: 35986704] [Full Text: https://doi.org/10.1111/bjd.21842]
Park, H.-S., Papanastasi, E., Blanchard, G., Chiticariu, E., Bachmann, D., Ploma nn, M., Morice-Picard, F., Vabres, P., Smahi, A., Huber, M., Pich, C., Hohl, D. ARP-T1-associated Bazex-Dupre-Christol syndrome is an inherited basal cell cancer with ciliary defects characteristic of ciliopathies. Commun. Biol. 4: 544, 2021. [PubMed: 33972689] [Full Text: https://doi.org/10.1038/s42003-021-02054-9]
Sha, Y., Liu, W., Li, L., Serafimovski, M., Isachenko, V., Li, Y., Chen, J., Zhao, B., Wang, Y., Wei, X. Pathogenic Variants in ACTRT1 Cause Acephalic Spermatozoa Syndrome. Front. Cell Dev. Biol. 9: 676246, 2021. [PubMed: 34422805] [Full Text: https://doi.org/10.3389/fcell.2021.676246]
Zhang, X.-Z., Wei, L.-L., Zhang, X.-H., Jin, H.-J., Chen, S.-R. Loss of perinuclear theca ACTRT1 causes acrosome detachment and severe male subfertility in mice. Development 149: dev200489, 2022. [PubMed: 35616329] [Full Text: https://doi.org/10.1242/dev.200489]