Alternative titles; symbols
HGNC Approved Gene Symbol: HSPA2
Cytogenetic location: 14q23.3 Genomic coordinates (GRCh38): 14:64,535,905-64,543,237 (from NCBI)
Bonnycastle et al. (1994) isolated a genomic clone for HSPA2 and found that it has a single open reading frame of 1,917 basepairs that encodes a 639-amino acid protein with a predicted molecular mass of 70,030 Da. Analysis of the sequence indicated that HSPA2 is the human homolog of the murine Hsp70-2 gene, with 91.7% identity in the nucleotide coding sequence and 98.2% in the corresponding amino acid sequence. HSPA2 has less amino acid homology to the other members of the human HSP70 gene family. HSPA2 is constitutively expressed in most tissues, with very high levels in testis and skeletal muscle.
Roux et al. (1994) also cloned the HSPA2 gene, using a genomic probe derived from one of the HSP genes in the major histocompatibility complex (MHC) on chromosome 6, which had previously been shown to detect sequences on chromosome 14 as well. HSPA2 is expressed abundantly in muscle, heart, esophagus, and brain, and to a lesser extent in testis.
Using Western blot analysis, Son et al. (1999) found significant expression of a 70-kD HSPA2 protein in testis, but only low expression in testis with Sertoli cell-only syndrome (see 305700). A small amount of HSPA2 was detected in breast, stomach, prostate, colon, liver, ovary, and epididymis. Immunohistochemical analysis of normal testis detected HSPA2 in spermatocytes and spermatids with normal spermatogenesis, whereas little to no immunoreactivity was detected in testis with Sertoli cell-only syndrome.
Huszar et al. (2000) determined that HSPA2 is identical to sperm CKM, a marker of sperm maturity and function. Immunohistochemical analysis detected weak expression of HSPA2 in spermatocytes and stronger expression in spermatids and in the tail of mature sperm.
During spermiogenesis, both cytoplasmic extrusion and plasma membrane remodeling, which facilitate the formation of the zona pellucida-binding site, involve major intrasperm protein transport. Huszar et al. (2000) noted that immature human sperm, which fail to express HSPA2, show cytoplasmic retention and lack zona pellucida binding. They suggested that HSPA2 may be critical to sperm maturation through its role as a protein chaperone.
Rohde et al. (2005) found elevated expression of HSP70-2 in 5 of 16 (31%) and 4 of 9 (44%) samples from primary and metastatic breast cancer tissue, respectively, compared with 13 samples from adjacent normal breast tissue. Cancer cells depleted of HSP70 (HSPA1A; 140550) and HSP70-2 by small interfering RNA displayed strikingly different morphologies (detached and round vs flat senescent-like), cell cycle distribution (G2/M vs G1 arrest), and gene expression profiles. Concomitant depletion of HSP70 and HSP70-2 had a synergistic antiproliferative effect on cancer cells.
Several heat-shock protein genes, such as HSPA1, are located in the MHC on chromosome 6. However, the HSPA2 gene is located on chromosome 14q22-q24 (Harrison et al., 1987). By fluorescence in situ hybridization, Bonnycastle et al. (1994) mapped a 670-kb YAC containing HSPA2 to chromosome 14q24.1. Roux et al. (1994) localized HSPA2 to chromosome 14q22 by study of a somatic cell hybrid panel and by FISH analysis. Hunt et al. (1993) found that the corresponding gene in the mouse is located in a region of chromosome 12 homologous to human chromosome 14.
For a discussion of a possible association between variation in the HSPA2 gene and noise-induced hearing loss, see 613035.
Dix et al. (1996) showed that female homozygous knockout mice for Hsp70-2 undergo normal meiosis and are fertile. In contrast, homozygous male knockout mice lacked postmeiotic spermatids and mature sperm and were infertile. Hsp70-2 is normally associated with synaptonemal complexes in the nuclei of meiotic spermatocytes. In the male knockouts, these structures were abnormal by late prophase. Dix et al. (1996) observed also a large increase in spermatocyte apoptosis.
Bonnycastle, L. L. C., Yu, C.-E., Hunt, C. R., Trask, B. J., Clancy, K. P., Weber, J. L., Patterson, D., Schellenberg, G. D. Cloning, sequencing, and mapping of the human chromosome 14 heat shock protein gene (HSPA2). Genomics 23: 85-93, 1994. [PubMed: 7829106] [Full Text: https://doi.org/10.1006/geno.1994.1462]
Dix, D. J., Allen, J. W., Collins, B. W., Mori, C., Nakamura, N., Poorman-Allen, P., Goulding, E. H., Eddy, E. M. Targeted gene disruption of Hsp70-2 results in failed meiosis, germ cell apoptosis, and male infertility. Proc. Nat. Acad. Sci. 93: 3264-3268, 1996. [PubMed: 8622925] [Full Text: https://doi.org/10.1073/pnas.93.8.3264]
Harrison, G. S., Drabkin, H. A., Kao, F.-T., Hartz, J., Hart, I. M., Chu, E. H. Y., Wu, B. J., Morimoto, R. I. Chromosomal location of human genes encoding major heat-shock protein HSP70. Somat. Cell Molec. Genet. 13: 119-130, 1987. [PubMed: 3470951] [Full Text: https://doi.org/10.1007/BF01534692]
Hunt, C. R., Gasser, D. L., Chaplin, D. D., Pierce, J. C., Kozak, C. A. Chromosomal localization of five murine HSP70 gene family members: Hsp70-1, Hsp70-2, Hsp70-3, Hsc70t and Grp78. Genomics 16: 193-198, 1993. [PubMed: 8486356] [Full Text: https://doi.org/10.1006/geno.1993.1158]
Huszar, G., Stone, K., Dix, D., Vigue, L. Putative creatine kinase M-isoform in human sperm is identified as the 70-kilodalton heat shock protein HspA2. Biol. Reprod. 63: 925-932, 2000. [PubMed: 10952940] [Full Text: https://doi.org/10.1095/biolreprod63.3.925]
Rohde, M., Daugaard, M., Jensen, M. H., Helin, K., Nylandsted, J., Jaattela, M. Members of the heat-shock protein 70 family promote cancer cell growth by distinct mechanisms. Genes Dev. 19: 570-582, 2005. [PubMed: 15741319] [Full Text: https://doi.org/10.1101/gad.305405]
Roux, A.-F., Nguyen, V. T. T., Squire, J. A., Cox, D. W. A heat shock gene at 14q22: mapping and expression. Hum. Molec. Genet. 3: 1819-1822, 1994. [PubMed: 7849706] [Full Text: https://doi.org/10.1093/hmg/3.10.1819]
Son, W.-Y., Hwang, S.-H., Han, C.-T., Lee, J.-H., Kim, S., Kim, Y. C. Specific expression of heat shock protein HspA2 in human male germ cells. Molec. Hum. Reprod. 5: 1122-1126, 1999. [PubMed: 10587366] [Full Text: https://doi.org/10.1093/molehr/5.12.1122]