Alternative titles; symbols
HGNC Approved Gene Symbol: ACTN4
Cytogenetic location: 19q13.2 Genomic coordinates (GRCh38): 19:38,647,649-38,731,589 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.2 | Glomerulosclerosis, focal segmental, 1 | 603278 | Autosomal dominant | 3 |
Honda et al. (1998) identified a novel actin-bundling protein associated with cell motility and cancer invasion.
Using a yeast 2-hybrid screen for proteins that interact with RNF22 (605493), El-Husseini et al. (2000) isolated an ACTN4 cDNA from a rat brain library. The rat ACTN4 sequence contained an additional N-terminal 27 amino acids compared with the human sequence reported by Honda et al. (1998). The additional sequence is consistent with another human sequence deposited in GenBank (U48734), leading El-Husseini et al. (2000) to conclude that there are multiple isoforms of ACTN4.
Using immunohistochemistry, El-Husseini et al. (2000) showed that rat RNF22 and ACTN4 are expressed in a punctate pattern throughout the cytoplasm and neuritic processes of differentiated PC12 cells. They concluded that the isoform of ACTN4 they identified may act to anchor microfilaments to various cellular structures.
Alpha-actinin is highly expressed in the glomerular podocyte, is important in nonmuscle cytoskeletal function, and is upregulated early in the course of some animal models of nephrotic syndrome (Kaplan et al., 2000).
Using in vitro binding assays, Patrie et al. (2002) showed that the fifth PDZ domain of mouse Magi1 (BAIAP1; 602625) interacted with the C terminus of rat alpha-actinin-4. Exogenously expressed human synaptopodin (608155) and rat alpha-actinin-4 colocalized with endogenous Magi1 at tight junctions of canine kidney epithelial cells.
By sequence analysis, Kaplan et al. (2000) mapped the ACTN4 gene to chromosome 19q13.
Focal segmental glomerulosclerosis (see FSGS1, 603278) is a common, nonspecific renal lesion. Although it is often secondary to other disorders, including HIV infection, obesity, hypertension, and diabetes, FSGS also appears as an isolated idiopathic condition which is inherited as an autosomal dominant. The phenotype had been mapped to 19q13. FSGS is characterized by increased urinary protein excretion and decreasing kidney function. Often, renal insufficiency in affected patients progresses to end-stage renal failure, a highly morbid state requiring either dialysis therapy or kidney transplantation. Kaplan et al. (2000) identified mutations in the gene encoding ACTN4 (604638.0001-604638.0004), an actin-filament crosslinking protein, as the cause of the disorder in 3 families with an autosomal dominant form of FSGS. They found that in vitro, mutant alpha-actinin-4 bound filamentous actin more strongly than did wildtype alpha-actinin-4. Regulation of the actin cytoskeleton of glomerular podocytes may be altered in this group of patients. The results had implications for understanding the role of the cytoskeleton in the pathophysiology of kidney disease and may be relevant to an understanding of the genetic basis of susceptibility to kidney damage.
Weins et al. (2007) stated that ACTN4 proteins with disease-causing mutations form aggregates with F-actin in human and mouse podocytes. Using knockin mice homozygous for a disease-causing mutation in human ACTN4, lys255 to glu (K255E), they showed that these aggregates were associated with the actin cytoskeleton. The mutation exposed a buried actin-binding site in ACTN4 that increased its actin-binding affinity, abolished its Ca(2+) regulation in vitro, and mislocalized it from actin stress fibers and focal adhesions in vivo. In vitro, actin filaments crosslinked by mutant ACTN4 exhibited changes of structural and biomechanical properties compared with wildtype ACTN4.
In a 13-year-old German girl with FSGS1, Bartram et al. (2016) identified a de novo heterozygous missense mutation in the ACTN4 gene (G195D; 604638.0004). The mutation was found by gene panel analysis and confirmed by Sanger sequencing. The mutant protein had altered localization and formed multiple F-actin-positive aggregates. Proteomic analysis of patient cells showed disturbances in the ACTN4 interactome with dysregulation of LIM domain proteins, which are important modular regulators of cell adhesion.
Echchakir et al. (2001) identified an antigen recognized on a human large cell carcinoma by an autologous tumor-specific cytolytic T lymphocyte (CTL) clone that was derived from mononuclear cells infiltrating the primary tumor in a lung cancer patient. The antigenic peptide was presented by HLA-A2 molecules and was encoded by the ACTN4 gene, which is expressed ubiquitously. In the tumor cells, a point mutation generated an amino acid change that is essential for recognition by the CTLs. The mutation was not found in ACTN4 cDNA sequences from about 50 lung carcinoma cell lines, suggesting that it was unique to this patient. Although the patient did not receive chemotherapy or radiotherapy, he remained without evidence of tumor after resection of the primary lesion in 1996. Anti-alpha-actinin-4 CTLs were derived from blood samples collected from the patient in 1998 and 2000. It is possible that these CTLs, recognizing a truly tumor-specific antigen, played a role in the clinical evolution of this lung cancer patient.
Kos et al. (2003) developed Actn4-deficient mice which showed progressive proteinuria, glomerular disease, and death by several months of age. Light microscopy revealed extensive glomerular disease and proteinaceous casts; electron microscopy showed focal areas of podocyte foot-process effacement in young mice and diffuse effacement and globally disrupted podocyte morphology in older mice. Histologic examination showed abnormalities only in the kidneys. Cell motility, as measured by lymphocyte chemotaxis assays, was increased in the absence of Actn4. Kos et al. (2003) concluded that ACTN4 is required for normal glomerular function and is involved in the regulation of cell movement. They also noted that the nonsarcomeric forms of actinin, ACTN1 (102575) and ACTN4, both found in the kidney, are not functionally redundant.
In affected individuals in a family with focal segmental glomerulosclerosis that mapped to 19q (FSGS1; 603278), Kaplan et al. (2000) found a lys228-to-gly (K228G) mutation caused by a 682A-G nucleotide substitution in the ACTN4 RNA. The disease in this family, like that in 2 others studied, showed a mild increase in urine protein excretion starting in the teenage years or later, slowly progressive renal dysfunction, and the development of end-stage renal failure in some affected individuals. Two individuals in this family carrying the lys228-to-glu allele had no clinical symptoms.
Kaplan et al. (2000) found that affected members in their family with focal segmental glomerulosclerosis mapping to 19q13 (FSGS1; 603278) had a thr232-to-ile (T232I) mutation in the ACTN4 gene, caused by a 695C-T transition. The family contained 4 individuals carrying the disease-associated allele who had no proteinuria.
Kaplan et al. (2000) studied a family in which affected members with focal segmental glomerulosclerosis (FSGS1; 603278) had a ser235-to-pro (S235P) mutation due to a 703T-C transition in the ACTN4 gene.
In a 13-year-old German girl with focal segmental glomerulosclerosis-1 (FSGS1; 603278), Bartram et al. (2016) identified a de novo heterozygous c.584G-A transition in the ACTN4 gene, resulting in a gly195-to-asp (G195D) substitution at a highly conserved residue in one of the CH domains. The mutation, which was found by gene panel analysis and confirmed by Sanger sequencing, was not found in large public whole exome sequencing databases or in 511 in-house exomes. Introduction of the mutation into podocytes showed that the mutant protein had altered localization compared to wildtype and formed multiple F-actin-positive aggregates. Renal epithelial cells derived from the patient and transfected HEK293 cells showed reduced expression of the ACTN4 protein, resulting from increased ubiquitination and subsequent clearance of the mutant protein. Proteomic analysis of patient cells showed disturbances in the ACTN4 interactome with dysregulation of LIM domain proteins, which are important modular regulators of cell adhesion.
Bartram, M. P., Habbig, S., Pahmeyer, C., Hohne, M., Weber, L. T., Thiele, H., Altmuller, J., Kottoor, N., Wenzel, A., Krueger, M., Schermer, B., Benzing, T., Rinschen, M. M., Beck, B. B. Three-layered proteomic characterization of a novel ACTN4 mutation unravels its pathogenic potential in FSGS. Hum. Molec. Genet. 25: 1152-1164, 2016. [PubMed: 26740551] [Full Text: https://doi.org/10.1093/hmg/ddv638]
Echchakir, H., Mami-Chouaib, F., Vergnon, I., Baurain, J.-F., Karanikas, V., Chouaib, S., Coulie, P. G. A point mutation in the alpha-actinin-4 gene generates an antigenic peptide recognized by autologous cytolytic T lymphocytes on a human lung carcinoma. Cancer Res. 61: 4078-4083, 2001. [PubMed: 11358829]
El-Husseini, A. E., Kwasnicka, D., Yamada, T., Hirohashi, S., Vincent, S. R. BERP, a novel ring finger protein, binds to alpha-actinin-4. Biochem. Biophys. Res. Commun. 267: 906-911, 2000. [PubMed: 10673389] [Full Text: https://doi.org/10.1006/bbrc.1999.2045]
Honda, K., Yamada, T., Endo, R., Ino, Y., Gotoh, M., Tsuda, H., Yamada, Y., Chiba, H., Hirohashi, S. Actinin-4, a novel actin-bundling protein associated with cell motility and cancer invasion. J. Cell Biol. 140: 1383-1393, 1998. Note: Erratum: J. Cell Biol. 143: 277 only, 1998. [PubMed: 9508771] [Full Text: https://doi.org/10.1083/jcb.140.6.1383]
Kaplan, J. M., Kim, S. H., North, K. N., Rennke, H., Correia, L. A., Tong, H.-Q., Mathis, B. J., Rodriguez-Perez, J.-C., Allen, P. G., Beggs, A. H., Pollak, M. R. Mutations in ACTN4, encoding alpha-actinin-4, cause familial focal segmental glomerulosclerosis. Nature Genet. 24: 251-256, 2000. [PubMed: 10700177] [Full Text: https://doi.org/10.1038/73456]
Kos, C. H., Le, T. C., Sinha, S., Henderson, J. M., Kim, S. H., Sugimoto, H., Kalluri, R., Gerszten, R. E., Pollak, M. R. Mice deficient in alpha-actinin-4 have severe glomerular disease. J. Clin. Invest. 111: 1683-1690, 2003. [PubMed: 12782671] [Full Text: https://doi.org/10.1172/JCI17988]
Patrie, K. M., Drescher, A. J., Welihinda, A., Mundel, P., Margolis, B. Interaction of two actin-binding proteins, synaptopodin and alpha-actinin-4, with the tight junction protein MAGI-1. J. Biol. Chem. 277: 30183-30190, 2002. [PubMed: 12042308] [Full Text: https://doi.org/10.1074/jbc.M203072200]
Weins, A., Schlondorff, J. S., Nakamura, F., Denker, B. M., Hartwig, J. H., Stossel, T. P., Pollak, M. R. Disease-associated mutant alpha-actinin-4 reveals a mechanism for regulating its F-actin-binding affinity. Proc. Nat. Acad. Sci. 104: 16080-16085, 2007. [PubMed: 17901210] [Full Text: https://doi.org/10.1073/pnas.0702451104]