HGNC Approved Gene Symbol: ACTL7A
Cytogenetic location: 9q31.3 Genomic coordinates (GRCh38) : 9:108,862,266-108,863,756 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.3 | Spermatogenic failure 86 | 620499 | Autosomal recessive | 3 |
Actins (e.g., 102610) and actin-related proteins (ARPs) are members of a superfamily of proteins that have an actin fold, which is an ATP-binding cleft, as the common feature. ARPs are significantly longer than conventional actins, with the difference in length usually accounted for by peptide insertions within the more divergent protein regions surrounding the ATP-binding cleft (Chadwick et al., 1999).
By cDNA selection and direct genomic sequencing from the familial dysautonomia (DYS; 223900) candidate region in 9q31, Chadwick et al. (1999) identified the ACTL7A gene. The authors found that the ACTL7A and ACTL7B (604304) genes are intronless and are located approximately 4 kb apart in a head-to-head orientation. The open reading frame of the ACTL7A gene encodes a predicted 435-amino acid member of the ARP family. As with other ARPs, ACTL7A is significantly longer than conventional actins. However, unlike other ARPs, the difference in size of ACTL7A is not due to insertions within the protein regions surrounding the ATP-binding cleft, but rather is caused by an extension of the N-terminal region. ACTL7A contains a single conserved cAMP/cGMP-dependent phosphorylation site, several conserved protein kinase C phosphorylation sites, and a leucine zipper consensus sequence. Human ACTL7A shares greater than 86% amino acid identity with mouse Actl7a, which the authors also identified. Northern blot analysis detected a prominent 1.8-kb ACTL7A transcript in human adult testis and a 1.2-kb ACTL7A transcript in all other human tissues, with the highest expression in heart. Based on mutational analysis of the ACTL7A gene in patients with dysautonomia, Chadwick et al. (1999) concluded that ACTL7A is unlikely to be involved in the pathogenesis of this disorder.
By immunostaining analysis, Dai et al. (2021) found that ACTL9 (619251) and ACTL7A colocalized in the acrosomal and equatorial segments of human sperm. Further analysis indicated that ACTL9 and ACTL7A colocalized in the perinuclear theca to participate in acrosomal anchoring. Coimmunoprecipitation assays in transfected HEK293 cells confirmed that ACTL9 interacted with ACTL7A.
Using a somatic cell hybrid mapping panel and genomic sequence analysis, Chadwick et al. (1999) localized the ACTL7A cDNA to 9q within the region for familial dysautonomia on 9q31. By linkage analysis using an interspecific backcross, Chadwick et al. (1999) mapped the mouse Actl7a gene to chromosome 4, in a region showing homology of synteny with human 9q31.
In 2 Chinese brothers from a consanguineous family with spermatogenic failure manifest as infertility due to acrosomal defects, fertilization failure, and early embryonic arrest (SPGF86; 620499), Xin et al. (2020) performed whole-exome sequencing (WES) and identified homozygosity for a missense mutation in the ACTL7A gene (A245T; 604303.0001). Their unaffected parents were heterozygous for the mutation, which was present at very low minor allele frequency in the gnomAD database (4.068 x 10(-6)), only in heterozygosity. ACTL7A was absent from patient sperm. In addition, the amount of the sperm-borne oocyte activating factor PLCZ1 (608075) was markedly reduced in patient sperm, and was detected only in the acrosome and not the equatorial region, which is the area that first fuses with the oocyte. The authors concluded that the reduced amount and altered distribution of PLCZ1 might be responsible for the fertilization and developmental failure observed in oocytes and embryos fertilized with patient sperm using artificial oocyte activation.
In a 26-year-old Chinese man with infertility due to acrosomal defects resulting in total fertilization failure, Wang et al. (2021) identified compound heterozygosity for mutations in the ACTL7A gene: an R155X substitution (604303.0002) and a G362R substitution (604303.0003). His unaffected parents were each heterozygous for 1 of the mutations, which were not found in the East Asian populations of public variant databases. Immunofluorescence analysis showed that ACTL7A signal was almost absent in patient sperm. The authors also observed markedly reduced levels of the key sperm-borne oocyte activation factor PLCZ1 in patient sperm and, citing the similar findings of Xin et al. (2020), suggested that mutation in ACTL7A causes oocyte activation deficiency and fertilization failure due to reduced expression and abnormal localization of PLCZ1.
In a 28-year-old Chinese man with infertility due to acrosomal defects resulting in total fertilization failure, Zhao et al. (2023) identified homozygosity for a nonsense mutation in the ACTL7A gene (S49X; 604303.0004). His consanguineous parents and 2 unaffected older sisters were heterozygous for the mutation, which was not found in East Asian populations of public variant databases. ACTLA7 expression in patient sperm was approximately 75% lower than that in control sperm.
In a Chinese man with infertility due to total fertilization failure, Hua et al. (2023) identified compound heterozygosity for the previously reported A245T mutation (604303.0001) and another missense mutation in the ACTL7A gene (G246A; 604303.0005).
Using CRISPR-Cas9 technology, Xin et al. (2020) generated mice with a knockin missense mutation (A249T) in the mouse ortholog gene Actl7a. Testes of homozygous mutants showed a 30% reduction in Actl7a mRNA levels compared to those of wildtype mice, and there was complete absence of Actl7a protein in mutant testes and sperm. Homozygous males were infertile, whereas homozygous female mice could generate offspring and showed no obvious defects in fertility. Evaluation by light microscopy showed an apparently normal spermatogenic process. However, immunofluorescence analysis of mutant sperm showed nonuniform distribution of acrosomal markers, and a change from the normal sickle shape of the acrosome to a cap-like structure. Transmission electron microscopy (TEM) revealed detachment of the acrosome from the nuclear envelope of the sperm, similar to TEM findings in ACTL7A-deficient patients. In addition, observation of acrosome biogenesis under TEM showed abnormal development, with large and atypical proacrosomic vesicles during the Golgi phase that failed to fuse and accumulated, eventually causing the abnormal acrosome to detach from the nuclear envelope. The authors suggested that Actl7a might play an important role in the formation and fusion of Golgi-derived vesicles during acrosome biogenesis. Spermatozoa from the homozygous mutant mice failed to fertilize normal mouse oocytes by IVF or by ICSI. Western blot and immunofluorescence analysis showed a marked reduction in the amount of the sperm-borne oocyte activating factor Plcz1 (608075) in mutant sperm, and it was detected only in the acrosome and not the equatorial region, which is the area that first fuses with the oocyte. In addition, the acrosomal shape changed from the normal sickle shape to a cap-like structure. The authors concluded that the reduced amount and altered distribution of PLCZ1 might be responsible for the fertilization failure observed. Artificial oocyte activation using strontium chloride rendered mutant sperm capable of fertilizing oocytes, and the resulting embryos developed into viable pups after implantation.
In 2 Chinese brothers with infertility due to acrosomal defects, fertilization failure, and early embryonic arrest (SPGF86; 620499), Xin et al. (2020) identified homozygosity for a c.733G-A transition (c.733G-A, NM_006687) in the ACTLA7 gene, resulting in an ala245-to-thr (A245T) substitution at a highly conserved residue. Their consanguineous parents were heterozygous for the mutation, which was present at very low minor allele frequency in the gnomAD database (4.068 x 10(-6)), only in heterozygosity. Immunofluorescence assays of patient sperm revealed total absence of ACTL7A signals. In addition, signals for the sperm outer acrosomal membrane marker peanut agglutinin (PNA) and for the acrosome proteinase acrosin (ACR; 102480) showed nonuniform distribution in patient sperm. Western blot and immunofluorescence studies revealed a marked decrease in the amount of the key sperm-borne oocyte activation factor PLCZ1 (608075).
In a Chinese man (P4) with infertility due to total fertilization failure, Hua et al. (2023) identified compound heterozygosity for the A245T mutation and a c.737G-C transition in exon 1 of the ACTL7A gene, resulting in a gly246-to-ala (G246A; 604303.0005) substitution. His unaffected parents and a fertile brother were each heterozygous for 1 of the mutations. The G246A mutation was not found in the East Asian populations of the 1KGP, ExAC, or gnomAD databases.
In a 26-year-old Chinese man with infertility due to acrosomal defects and total fertilization failure (SPGF86; 620499), Wang et al. (2021) identified compound heterozygosity for mutations in the ACTL7A gene: a c.463C-T transition (c.463C-T, NM_006687) in exon 1, resulting in an arg155-to-ter (R155X) substitution, and a c.1084G-A transition in exon 1, resulting in a gly362-to-arg (G362R) substitution, both at conserved residues. His unaffected parents were each heterozygous for 1 of the mutations, neither of which was found in East Asian populations of public variant databases; both variants were present at very low minor allele frequency (0.000008 and 0.000016, respectively) in the general populations of the ExAC and gnomAD databases. Immunofluorescence analysis showed that ACTL7A signal was almost absent in patient sperm, and the signal for the subacrosomal layer marker PNA was aggregated and unevenly distributed. In addition, PLCZ1 (608075) signal was significantly decreased in patient sperm compared to control.
For discussion of the c.1084G-A transition (c.1084G-A, NM_006687) in exon 1 of the ACTL7A gene, resulting in a gly362-to-arg (G362R) substitution, that was found in compound heterozygous state in a 26-year-old Chinese man with infertility due to acrosomal defects and total fertilization failure (SPGF86; 620499) by Wang et al. (2021), see 604303.0002.
In a 28-year-old Chinese man (case 1) with infertility due to acrosomal defects and total fertilization failure (SPGF86; 620499), Zhao et al. (2023) identified homozygosity for a c.146C-G transversion in exon 1 of the ACTL7A gene, resulting in a ser49-to-ter (S49X) substitution and a protein lacking the functional actin domain. His consanguineous parents and 2 unaffected older sisters were heterozygous for the mutation, which was not found in the East Asian populations of the 1000 Genomes Project or gnomAD databases. ACTLA7 expression in patient sperm was approximately 75% lower than that in control sperm.
For discussion of the c.737G-C transition (c.737G-C, NM_006687) in exon 1 of the ACTL7A gene, resulting in a gly246-to-ala (G246A) substitution, that was found in compound heterozygous state in a Chinese man (P4) with infertility due to total fertilization failure (SPGF86; 620499) by Hua et al. (2023), see 604303.0001.
Chadwick, B. P., Mull, J., Helbling, L. A., Gill, S., Leyne, M., Robbins, C. M., Pinkett, H. W., Makalowska, I., Maayan, C., Blumenfeld, A., Axelrod, F. B., Brownstein, M., Gusella, J. F., Slaugenhaupt, S. A. Cloning, mapping, and expression of two novel actin genes, actin-like-7A (ACTL7A) and actin-like-7B (ACTL7B), from the familial dysautonomia candidate region on 9q31. Genomics 58: 302-309, 1999. [PubMed: 10373328] [Full Text: https://doi.org/10.1006/geno.1999.5848]
Dai, J., Zhang, T., Guo, J., Zhou, Q., Gu, Y., Zhang, J., Hu, L., Zong, Y., Song, J., Zhang, S., Dai, C., Gong, F., Lu, G., Zheng, W., Lin, G. Homozygous pathogenic variants in ACTL9 cause fertilization failure and male infertility in humans and mice. Am. J. Hum. Genet. 108: 469-481, 2021. [PubMed: 33626338] [Full Text: https://doi.org/10.1016/j.ajhg.2021.02.004]
Hua, R., Xue, R., Liu, Y., Li, Y., Sha, X., Li, K., Gao, Y., Shen, Q., Lv, M., Xu, Y., Zhang, Z., He, X., Cao, Y., Wu, H. ACROSIN deficiency causes total fertilization failure in humans by preventing the sperm from penetrating the zona pellucida. Hum. Reprod. 38: 1213-1223, 2023. [PubMed: 37004249] [Full Text: https://doi.org/10.1093/humrep/dead059]
Wang, J., Zhang, J., Sun, X., Lin, Y., Cai, L., Cui, Y., Liu, J., Liu, M., Yang, X. Novel bi-allelic variants in ACTL7A are associated with male infertility and total fertilization failure. Hum. Reprod. 36: 3161-3169, 2021. [PubMed: 34727571] [Full Text: https://doi.org/10.1093/humrep/deab228]
Xin, A., Qu, R., Chen, G., Zhang, L., Chen, J., Tao, C., Fu, J., Tang, J., Ru, Y., Chen, Y., Peng, X., Shi, H., Zhang, F., Sun, X. Disruption in ACTL7A causes acrosomal ultrastructural defects in human and mouse sperm as a novel male factor inducing early embryonic arrest. Sci. Adv. 6: eaaz4796, 2020. [PubMed: 32923619] [Full Text: https://doi.org/10.1126/sciadv.aaz4796]
Zhao, S., Cui, Y., Guo, S., Liu, B., Bian, Y., Zhao, S., Chen, Z., Zhao, H. Novel variants in ACTL7A and PLCZ1 are associated with male infertility and total fertilization failure. Clin. Genet. 103: 603-608, 2023. [PubMed: 36593593] [Full Text: https://doi.org/10.1111/cge.14293]