HGNC Approved Gene Symbol: ACTN1
Cytogenetic location: 14q24.1 Genomic coordinates (GRCh38): 14:68,874,128-68,979,302 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q24.1 | Bleeding disorder, platelet-type, 15 | 615193 | Autosomal dominant | 3 |
Alpha-actinin was initially isolated from rabbit skeletal muscle as a factor that induces the gelation of F-actin and promotes the superprecipitation of actomyosin. Subsequently, a number of different isoforms were isolated from both muscle and nonmuscle cells and from a wide variety of organisms. The native molecule is thought to be a homodimer of 97-kD subunits arranged in antiparallel fashion. In myofibrillar cells, alpha-actinin constitutes a major component of Z discs in striated muscle and of the functionally analogous dense bodies and dense plaques in smooth muscle. In nonmuscle cells, it is distributed along microfilament bundles and is thought to mediate their attachment to the membrane at adherens-type junctions (Youssoufian et al., 1990).
Youssoufian et al. (1990) cloned and characterized a full-length cDNA encoding the human cytoskeletal isoform. The gene encodes 891 amino acids with 96 to 98% sequence identity at the amino acid level to chicken nonskeletal muscle alpha-actinin. Transient expression in COS cells produced a protein of about 104 kD.
Kanchanawong et al. (2010) used 3-dimensional super-resolution fluorescence microscopy to map nanoscale protein organization in focal adhesions. Their results revealed that integrins and actin are vertically separated by an approximately 40-nm focal adhesion core region consisting of multiple protein-specific strata: a membrane-apposed integrin signaling layer containing integrin cytoplasmic tails (see 193210), focal adhesion kinase (600758), and paxillin (602505); an intermediate force-transduction layer containing talin (186745) and vinculin (193065); and an uppermost actin-regulatory layer containing zyxin (602002), vasodilator-stimulated phosphoprotein (601703), and alpha-actinin. By localizing amino- and carboxy-terminally tagged talins, Kanchanawong et al. (2010) revealed talin's polarized orientation, indicative of a role in organizing the focal adhesion strata. Kanchanawong et al. (2010) concluded that their composite multilaminar protein architecture provided a molecular blueprint for understanding focal adhesion functions.
By analysis of somatic cell hybrids and by in situ hybridization, Youssoufian et al. (1990) mapped the gene to 14q22-q24. Pulsed-field gel analysis of genomic DNA showed that the ACTN1 gene and that for erythroid beta-spectrin (SPTB; 182870) are located in the same restriction fragment. This finding is of great interest because of the structural homology between spectrin and actinin.
In affected members from 6 unrelated Japanese families with autosomal dominant platelet-type bleeding disorder-15 (BDPLT15; 615193), manifest mainly as macrothrombocytopenia with little bleeding, Kunishima et al. (2013) identified 6 different heterozygous missense mutations in the ACTN1 gene (102575.0001-102575.0006). Three of the mutations were identified by exome sequencing. ACTN1 mutations were found in 5.5% of the dominant forms of congenital macrothrombocytopenia in their cohort, and represented the fourth most common cause of the disorder in Japanese individuals. Expression of the mutations in Chinese hamster ovary (CHO) cells showed that the mutant proteins caused varying degrees of disorganization of the actin filaments, with mutant ACTN1 colocalized with less fine, shortened actin filaments, and unbound ACTN1 coarsely distributed within the cytoplasm. Expression of 2 of the mutations (V105I, 102575.0001 and G32K, 102575.0002) in mouse fetal liver-derived megakaryocytes resulted in less organization of the circumferential actin-filament network compared to controls. The findings suggested that ACTN1 mutations dominantly affected the actin filament assembly, likely resulting in abnormal cytoskeletal organization. Examination of proplatelet formation from megakaryocytes showed that the G32K and V105I mutations did not change the rate of proplatelet formation or platelet production, but did reduce the number of proplatelet tips and increase the size of proplatelet tips from megakaryocytes.
In a Japanese mother and daughter with platelet-type bleeding disorder-15 (BDPLT15; 615193) manifest as macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous 313G-A transition in exon 3 of the ACTN1 gene, resulting in a val105-to-ile (V105I) substitution at a highly conserved residue in the functional N-terminal actin-binding domain. The mutation, which was found by exome sequencing, was not found in several large control databases or in 120 control individuals. Expression of the mutation in CHO cells showed that the mutant protein caused varying degrees of disorganization of the actin filaments, with mutant ACTN1 colocalized with less fine, shortened actin filaments and unbound ACTN1 coarsely distributed within the cytoplasm. Expression of the mutation in mouse fetal liver-derived megakaryocytes showed less organization of the circumferential actin-filament network compared to controls. The findings suggested that the mutation dominantly affected the actin filament assembly, likely resulting in abnormal cytoskeletal organization. Examination of proplatelet formation from megakaryocytes showed that the mutation did not change the rate of proplatelet formation or platelet production, but did reduce the number of proplatelet tips and increase the size of proplatelet tips from megakaryocytes.
In a Japanese father and his 2 sons with BDPLT15 (615193) manifest as macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous 94C-A transversion in exon 1 of the ACTN1 gene, resulting in a gln32-to-lys (Q32K) substitution at a highly conserved residue in the functional N-terminal actin-binding domain. The mutation, which was found by exome sequencing, was not found in several large control databases or in 120 control individuals. Expression of the mutation in CHO cells showed that the mutant protein caused varying degrees of disorganization of the actin filaments, with mutant ACTN1 colocalized with less fine, shortened actin filaments and unbound ACTN1 coarsely distributed within the cytoplasm. Expression of the mutation in mouse fetal liver-derived megakaryocytes showed less organization of the circumferential actin-filament network compared to controls. The findings suggested that the mutation dominantly affected the actin filament assembly, likely resulting in abnormal cytoskeletal organization. Examination of proplatelet formation from megakaryocytes showed that the mutation did not change the rate of proplatelet formation or platelet production, but did reduce the number of proplatelet tips and increase the size of proplatelet tips from megakaryocytes.
In a Japanese mother and son with BDPLT15 (615193) manifest as macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous 2255G-A transition in exon 18 of the ACTN1 gene, resulting in an arg752-to-gln (R752Q) substitution at a highly conserved residue in the functional C-terminal calmodulin-like domain. The mutation, which was identified by sequencing, was not found in several large control databases or in 120 control individuals.
In a Japanese father and his 2 daughters with BDPLT15 (615193) manifest as macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous 137G-A transition in exon 2 of the ACTN1 gene, resulting in an arg46-to-gln (R46Q) substitution at a highly conserved residue in the functional N-terminal actin-binding domain. The mutation was not found in 120 control individuals.
In a Japanese patient with BDPLT15 (615193) manifest as macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous 2212C-T transition in exon 18 of the ACTN1 gene, resulting in an arg738-to-trp (R738W) substitution at a highly conserved residue in the functional C-terminal calmodulin-binding domain. There was a family history of the disorder, but DNA from other family members was not available. The mutation was not found in 120 control individuals.
In a Japanese mother and daughter with BDPLT15 (615193) manifest as macrothrombocytopenia, Kunishima et al. (2013) identified a heterozygous 673G-A transition in exon 7 of the ACTN1 gene, resulting in a glu225-to-lys (E225K) substitution at a highly conserved residue in the functional N-terminal actin-binding domain. The mutation was not found in 120 control individuals.
Kanchanawong, P., Shtengel, G., Pasapera, A. M., Ramko, E. B., Davidson, M. W., Hess, H. F., Waterman, C. M. Nanoscale architecture of integrin-based cell adhesions. Nature 468: 580-584, 2010. [PubMed: 21107430] [Full Text: https://doi.org/10.1038/nature09621]
Kunishima, S., Okuno, Y., Yoshida, K., Shiraishi, Y., Sanada, M., Muramatsu, H., Chiba, K., Tanaka, H., Miyazaki, K., Sakai, M., Ohtake, M., Kobayashi, R., Iguchi, A., Niimi, G., Otsu, M., Takahashi, Y., Miyano, S., Saito, H., Kojima, S., Ogawa, S. ACTN1 mutations cause congenital macrothrombocytopenia. Am. J. Hum. Genet. 92: 431-438, 2013. [PubMed: 23434115] [Full Text: https://doi.org/10.1016/j.ajhg.2013.01.015]
Youssoufian, H., McAfee, M., Kwiatkowski, D. J. Cloning and chromosomal localization of the human cytoskeletal alpha-actinin gene reveals linkage to the beta-spectrin gene. Am. J. Hum. Genet. 47: 62-72, 1990. [PubMed: 2349951]