Alternative titles; symbols
HGNC Approved Gene Symbol: HSPA1L
Cytogenetic location: 6p21.33 Genomic coordinates (GRCh38) : 6:31,809,619-31,815,283 (from NCBI)
The human HSP70, or HSPA, multigene family encodes several highly conserved 70-kD heat-shock proteins that vary in their inducibility in response to metabolic stress. Sargent et al. (1989) identified the HSP70-HOM gene as a region with similarity to HSP70-1 (HSPA1A; 140550) that was located approximately 4 kb telomeric to HSP70-1 in the class III region of the major histocompatibility complex on 6p21.3. Milner and Campbell (1990) defined this homologous region as a gene of the HSP70 family. They found that the HSP70-HOM gene lacks introns. The predicted 641-amino acid HSP70-HOM protein is 90%, 84%, and 79% identical to the HSP70-1, HSC70 (HSPA8; 600816), and HSP70B-prime (HSPA6; 140555) proteins, respectively; the sequences differ most in the C-terminal 100 amino acids. Northern blot analysis of HeLa cell RNA detected an approximately 3-kb HSP70-HOM transcript that was expressed constitutively at a low level but was not induced by heat shock.
Hasson et al. (2013) elucidated regulators that have an impact on parkin (PARK2; 602544) translocation to damaged mitochondria with genomewide small interfering RNA (siRNA) screens coupled to high-content microscopy. Screening yielded gene candidates involved in diverse cellular processes that were subsequently validated in low-throughput assays. This led to characterization of TOMM7 (607980) as essential for stabilizing PINK1 (608309) on the outer mitochondrial membrane following mitochondrial damage. Hasson et al. (2013) also discovered that HSPA1L and BAG4 (603884) have mutually opposing roles in the regulation of parkin translocation. The screens revealed that SIAH3 (615609), found to localize to mitochondria, inhibits PINK1 accumulation after mitochondrial insult, reducing parkin translocation.
Milner and Campbell (1992) investigated the presence of sequence variation in the HSP70-HOM gene among different HLA haplotypes. They identified a T-to-C transition in a number of haplotypes that results in a met-to-thr substitution at position 493 (M493T), which is located within the proposed peptide-binding site of HSP70 proteins.
Abacavir is a commonly used nucleoside analog with potent antiviral activity against HIV-1. Approximately 5 to 9% of patients treated with abacavir develop a hypersensitivity reaction characterized by multisystem involvement that can be fatal in rare cases (Mallal et al., 2002; Hetherington et al., 2002). Martin et al. (2004) reported that the combination of HLA-B*5701 (see 142830) and a haplotypic M493T polymorphism of HSP70-HOM is highly predictive of abacavir hypersensitivity.
Spagnolo et al. (2007) found a strong association between the HSP70-HOM rs2075800 G allele and uveitis in patients with sarcoidosis (181000). Their study included 270 white patients with sarcoidosis, including 88 with sarcoid-related uveitis; 347 matched control subjects; and 181 patients with idiopathic interior or intermediate uveitis. The HSPA1L rs2075800 G allele frequency was higher in the sarcoid-uveitis group than in both the sarcoid-nonuveitis and control groups (83% vs 71%, OR, 2.00, P(c) = 0.01; and 83% vs 66%, OR, 2.45, P(c) = 0.00005, respectively). Similar results were observed when considering the carriage frequency of the associated haplotype (HSP70 haplotype 2) across the 3 study groups. In addition, the association was specific sarcoidosis, as the carriage of the G allele discriminated between sarcoid-related and idiopathic forms of uveitis.
For discussion of a possible association between variation in the HSPA2 gene and noise-induced hearing loss, see 613035.
Hasson, S. A., Kane, L. A., Yamano, K., Huang, C.-H., Sliter, D. A., Buehler, E., Wang, C., Heman-Ackah, S. M., Hessa, T., Guha, R., Martin, S. E., Youle, R. J. High-content genome-wide RNAi screens identify regulators of parkin upstream of mitophagy. Nature 504: 291-295, 2013. [PubMed: 24270810] [Full Text: https://doi.org/10.1038/nature12748]
Hetherington, S., Hughes, A. R., Mosteller, M., Shortino, D., Baker, K. L., Spreen, W., Lai, E., Davies, K., Handley, A., Dow, D. J., Fling, M. E., Stocum, M., Bowman, C., Thurmond, L. M., Roses, A. D. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. Lancet 359: 1121-1122, 2002. [PubMed: 11943262] [Full Text: https://doi.org/10.1016/S0140-6736(02)08158-8]
Mallal, S., Nolan, D., Witt, C., Masel, G., Martin, A. M., Moore, C., Sayer, D., Castley, A., Mamotte, C., Maxwell, D., James, I., Christiansen, F. T. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 359: 727-732, 2002. [PubMed: 11888582] [Full Text: https://doi.org/10.1016/s0140-6736(02)07873-x]
Martin, A. M., Nolan, D., Gaudieri, S., Almeida, C. A., Nolan, R., James, I., Carvalho, F., Phillips, E., Christiansen, F. T., Purcell, A. W., McCluskey, J., Mallal, S. Predisposition to abacavir hypersensitivity conferred by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proc. Nat. Acad. Sci. 101: 4180-4185, 2004. [PubMed: 15024131] [Full Text: https://doi.org/10.1073/pnas.0307067101]
Milner, C. M., Campbell, R. D. Structure and expression of the three MHC-linked HSP70 genes. Immunogenetics 32: 242-251, 1990. [PubMed: 1700760] [Full Text: https://doi.org/10.1007/BF00187095]
Milner, C. M., Campbell, R. D. Polymorphic analysis of the three MHC-linked HSP70 genes. Immunogenetics 36: 357-362, 1992. [PubMed: 1356099] [Full Text: https://doi.org/10.1007/BF00218042]
Sargent, C. A., Dunham, I., Trowsdale, J., Campbell, R. D. Human major histocompatibility complex contains genes for the major heat shock protein HSP70. Proc. Nat. Acad. Sci. 86: 1968-1972, 1989. [PubMed: 2538825] [Full Text: https://doi.org/10.1073/pnas.86.6.1968]
Spagnolo, P., Sato, H., Marshall, S. E., Antoniou, K. M., Ahmad, T., Wells, A. U., Ahad, M. A., Lightman, S., du Bois, R. M., Welsh, K. I. Association between heat shock protein 70/Hom genetic polymorphisms and uveitis in patients with sarcoidosis. Invest. Ophthal. Vis. Sci. 48: 3019-3025, 2007. [PubMed: 17591867] [Full Text: https://doi.org/10.1167/iovs.06-1485]