Alternative titles; symbols
HGNC Approved Gene Symbol: AHNAK
Cytogenetic location: 11q12.3 Genomic coordinates (GRCh38): 11:62,433,544-62,546,806 (from NCBI)
The AHNAK protein is involved in subsarcolemmal cytoarchitecture and membrane repair (Huang et al., 2008).
Neuroblastoma represents the most primitive neoplasm originating from migratory neural crest cells and apparently arises as a result of arrested differentiation. To identify genes whose transcription might be repressed during the genesis of neuroblastomas, Shtivelman and Bishop (1991) used subtractive cDNA cloning to detect genes expressed in human melanomas and pheochromocytomas but not in neuroblastomas. The first of these genes identified encoded the cell surface protein CD44 (107269), an integral membrane glycoprotein that is the principal receptor for hyaluronate on the cell surface. A second gene, originally designated PM227, attracted their attention because its expression appeared to be coordinated with that of CD44. Shtivelman et al. (1992) reported that PM227 encodes a protein whose exceptionally large size of 700 kD caused them to rename the gene AHNAK (meaning 'giant' in Hebrew). The amino acid sequence of AHNAK suggested secondary structure with a periodicity of 2.33 residues per turn. Individual chains could associate to form a 7- or 8-stranded barrel. The resulting structure would be a polyionic rod with length as great as 1.2 microns. Preliminary evidence indicated that the protein resides predominantly within the nucleus, but no function had been discerned. The highly conserved repeated elements were, for the most part, 128 amino acids long.
AHNAK is thought to be identical to desmoyokin (Hashimoto et al., 1993) which was first identified as a 680-kD desmosomal plaque protein in bovine muzzle epidermis.
By subcellular fractionation of mouse myocardium, Komuro et al. (2004) found that Ahnak colocalized with Ahnak2 (608570) in nuclei and myofibrillar aggregates that included Z-band material and in a vesicular fraction that included a T-tubule marker.
Using a panel of somatic cell hybrids and Southern blot analysis, Kudoh et al. (1995) mapped the human AHNAK/desmoyokin gene to chromosome 11. Fluorescence in situ hybridization experiments independently confirmed the chromosomal localization and refined it to band 11q12.
Courseaux et al. (1996) used a combination of methods to refine maps of an approximately 5-Mb region of 11q13. They proposed the following gene order: cen--PGA--FTH1--UGB--AHNAK--ROM1--MDU1--CHRM1--COX8--EMK1--FKBP2--PLCB3--[PYGM, ZFM1]--FAU--CAPN1--[MLK3, RELA]--FOSL1--SEA--CFL1--tel.
Huang et al. (2008) demonstrated that calpain-3 (CAPN3; 114240) and AHNAK colocalized at the I-band near the A-I junction in human skeletal muscle. Using COS-1 cells, they found that calpain-3 cleaved AHNAK and that this cleavage resulted in decreased levels of AHNAK. Studies of AHNAK fusion protein constructs showed that calpain-3 could cleave AHNAK at 2 sites in the N terminus and 3 sites in the C terminus, but not at the central M region. Cleavage of AHNAK disrupted its binding to dysferlin (DYSF; 603009) and myoferlin (FER1L3; 604603). Skeletal muscle from 4 patients with LGMD2A (253600) due to CAPN3 mutations showed increased levels of AHNAK at the sarcolemma and blood vessels. Huang et al. (2008) concluded that CAPN3 plays a role in the dysferlin protein complex and that disruption of CAPN3 function may affect muscle membrane repair and remodeling.
Komuro et al. (2004) disrupted the Ahnak gene in mice and found that Ahnak null animals were viable, grew and developed normally, and showed no obvious phenotype. They hypothesized that Ahnak2 may attenuate the effects of Ahnak deletion.
Matza et al. (2008) found that Ahnak1 -/- mice were highly susceptible to infection with Leishmania major. Ahnak -/- Cd4 (186940)-positive T cells proliferated poorly and produced little Il2 (147680). Calcium influx was reduced upon T-cell receptor (TCR; see 186880) stimulation, resulting in poor Nfat (see 600489) activation. Plasma membrane expression of Cav1.1 (CACNA1S; 114208) also required Ahnak1. Matza et al. (2008) concluded that AHNAK1 plays an essential role in Ca(2+) signaling through Cav1 channels in TCR-activated T cells.
Courseaux, A., Grosgeorge, J., Gaudray, P., Pannett, A. A. J., Forbes, S. A., Williamson, C., Bassett, D., Thakker, R. V., Teh, B. T., Farnebo, F., Shepherd, J., Skogseid, B., Larsson, C., Giraud, S., Zhang, C. X., Salandre, J., Calender, A. Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. Genomics 37: 354-365, 1996. [PubMed: 8938448]
Hashimoto, T., Amagai, M., Parry, D. A. D., Dixon, T. W., Tsukita, S., Tsukita, S., Miki, K., Sakai, K., Inokuchi, Y., Kudoh, J., Shimizu, N., Nishikawa, T. Desmoyokin, a 680 kDa keratinocyte plasma membrane-associated protein, is homologous to the protein encoded by human gene AHNAK. J. Cell. Sci. 105: 275-286, 1993. [PubMed: 8408266] [Full Text: https://doi.org/10.1242/jcs.105.2.275]
Huang, Y., de Morree, A., van Remoortere, A., Bushby, K., Frants, R. R., Dunnen, J. T., van der Maarel, S. Calpain 3 is a modulator of the dysferlin protein complex in skeletal muscle. Hum. Molec. Genet. 17: 1855-1866, 2008. [PubMed: 18334579] [Full Text: https://doi.org/10.1093/hmg/ddn081]
Komuro, A., Masuda, Y., Kobayashi, K., Babbitt, R., Gunel, M., Flavell, R. A., Marchesi, V. T. The AHNAKs are a class of giant propeller-like proteins that associate with calcium channel proteins of cardiomyocytes and other cells. Proc. Nat. Acad. Sci. 101: 4053-4058, 2004. [PubMed: 15007166] [Full Text: https://doi.org/10.1073/pnas.0308619101]
Kudoh, J., Wang, Y., Minoshima, S., Hashimoto, T., Amagai, M., Nishikawa, T., Shtivelman, E., Bishop, J. M., Shimizu, N. Localization of the human AHNAK/desmoyokin gene (AHNAK) to chromosome band 11q12 by somatic cell hybrid analysis and fluorescence in situ hybridization. Cytogenet. Cell Genet. 70: 218-220, 1995. [PubMed: 7789175] [Full Text: https://doi.org/10.1159/000134037]
Matza, D., Badou, A., Kobayashi, K. S., Goldsmith-Pestana, K., Masuda, Y., Komuro, A., McMahon-Pratt, D., Marchesi, V. T., Flavell, R. A. A scaffold protein, AHNAK1, is required for calcium signaling during T cell activation. Immunity 28: 64-74, 2008. [PubMed: 18191595] [Full Text: https://doi.org/10.1016/j.immuni.2007.11.020]
Shtivelman, E., Bishop, J. M. Expression of CD44 is repressed in neuroblastoma cells. Molec. Cell. Biol. 11: 5446-5453, 1991. [PubMed: 1922057] [Full Text: https://doi.org/10.1128/mcb.11.11.5446-5453.1991]
Shtivelman, E., Cohen, F. E., Bishop, J. M. A human gene (AHNAK) encoding an unusually large protein with a 1.2-micron polyionic rod structure. Proc. Nat. Acad. Sci. 89: 5472-5476, 1992. Note: Erratum: Proc. Nat. Acad. Sci. 90: 4328 only, 1993. [PubMed: 1608957] [Full Text: https://doi.org/10.1073/pnas.89.12.5472]