Alternative titles; symbols
HGNC Approved Gene Symbol: HSPD1
SNOMEDCT: 870284000;
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:197,486,584-197,500,274 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q33.1 | Leukodystrophy, hypomyelinating, 4 | 612233 | Autosomal recessive | 3 |
| Spastic paraplegia 13, autosomal dominant | 605280 | Autosomal dominant | 3 |
It had long been assumed that all information necessary for proper folding of proteins and their assembly into oligomeric complexes was contained within the primary sequence of the polypeptides and that no catalyst or other accessory proteins were involved in this process. However, this basic tenet of biochemistry was challenged by the discovery of chaperonins, which are involved in the folding and assembly of a number of different proteins (Cheng et al., 1989; Ellis, 1990; Rothman, 1989). Members of the chaperonin family include the GroEL protein of E. coli and HSP60, a protein present in eukaryotic cell mitochondria. In both prokaryotic and eukaryotic systems, synthesis of these proteins is induced in response to stresses, such as heat shock (Venner et al., 1990).
Venner et al. (1990) presented evidence of the existence of multiple copies of the HSP60 gene in the human. All except one of these genes are nonfunctional pseudogenes containing numerous changes such as base substitutions, insertions, and deletions.
Azem et al. (1994) performed chemical crosslinking and electron microscopy studies on bacterial chaperonins GroEL and GroES (HSPE1; 600141) to determine how they interact with unfolded proteins. GroEL is an oligomer of 14 identical 57.3-kD subunits, with a structure of 2 stacked heptameric rings arranged around a 2-fold axis of symmetry (Saibil et al., 1991). It appears as a hollow cylinder. In the presence of ATP, 2 GroES rings (each made of 7 identical 10.4-kD subunits) can successively bind a single GroEL core to make a functional symmetric heterodimer. Although the central core of GroEL is obstructed by the 2 GroES rings at each end, this heterodimer can stably bind and assist the refolding of the RuBisCo enzyme. While binding was thought to occur in the central cavity, these data indicate that unfolded proteins may bind and fold on the external envelope of some chaperonins (Azem et al., 1994). Schmidt et al. (1994) suggested that the symmetric chaperonin complex is functionally significant because complete folding of a nonnative substrate protein in the presence of GroEL and GroES occurs only in the presence of ATP, and not with ADP. Chaperonin-assisted folding occurs by a catalytic cycle in which one ATP is hydrolyzed by one ring of GroEL in a quantized manner with each turnover. Todd et al. (1994) proposed a unifying model for chaperonin-facilitated protein folding based on successive rounds of binding and release, and partitioning between committed and kinetically trapped intermediates.
Zal et al. (2004) examined the antigen recognition of CD4 (186940)-positive/CD28 (186760)-null T lymphocytes from 21 patients with acute coronary syndrome (ACS), 12 with chronic stable angina, and 9 healthy controls. CD4-positive/CD28-null cells from 12 of 21 patients with ACS reacted with HSPD1; no response was detected to human cytomegalovirus, Chlamydia pneumoniae, or oxidized LDL. CD4-positive/CD28-null cells from patients with chronic stable angina and controls did not react to any of the antigens. Zal et al. (2004) concluded that HSPD1 is an antigen recognized by CD4-positive/CD28-null T cells of patients with acute coronary syndrome and suggested that HSPD1-specific CD4-positive/CD28-null cells may contribute to vascular damage in these patients.
Using a luciferase-reporter assay, Hansen et al. (2003) demonstrated that the region between the HSP60 and HSP10 (600141) genes functions as a bidirectional promoter.
Tokuriki and Tawfik (2009) examined the ability of the E. coli GroEL/GroES (HSP10) chaperonins to buffer destabilizing and adaptive mutations. Mutational drifts performed in vitro with 4 different enzymes indicated the GroEL/GroES overexpression doubled the number of accumulating mutations, and promoted the folding of enzyme variants carrying mutations in the protein core and/or mutations with higher destabilizing effects. The divergence of modified enzymatic specificity occurred much faster under GroEL/GroES overexpression, in terms of the number of adapted variants (greater than or equal to 2-fold) and their improved specificity and activity (greater than or equal to 10-fold). Tokuriki and Tawfik (2009) concluded that protein stability is a major constraint in protein evolution, and that buffering mechanisms such as chaperonins are key in alleviating this constraint.
Venner et al. (1990) claimed that HSP60 is intronless. Hansen et al. (2003) presented the full sequence of the HSP60 and HSP10 genes. They found that both genes are linked head to head, comprising approximately 17 kb and consisting of 12 and 4 exons, respectively. The first exon of HSP60 is noncoding, and the first exon of HSP10 ends with the start codon.
By radiation hybrid analysis, Hansen et al. (2003) mapped the HSP60 gene between markers AFMA121YH1 and WI-10756 on chromosome 2. This localization and the position of 2 homologous fragments in the human genome assembly were consistent with the cytogenetic location 2q33.1.
Spastic paraplegia 13
Hereditary spastic paraplegia (SPG, HSP) represents a clinically and genetically heterogeneous group of neurodegenerative disorders that are characterized by progressive spasticity and weakness of the lower limbs. Seventeen different loci had been mapped, and the corresponding genes for 5 of these had been cloned and identified. Two of the 5 gene products--paraplegin (SPG7; 602783) and spastin (SPG4; 182601)--feature AAA+ domains and are predicted to possess chaperone activity. Paraplegin is the human homolog of a yeast protease/chaperone that is involved in mitochondrial protein quality control. The HSP60 gene maps to the same region, namely 2q33.1, as spastic paraplegia-13 (SPG13; 605280), as determined by Fontaine et al. (2000). Speculating that the mitochondrial chaperonin HSP60 or its co-chaperonin HSP10, which maps to the same region, might be the site of mutation(s) causing SPG13, Hansen et al. (2002) sequenced HSP60 in 2 affected members of the family with SPG13. They found that both were heterozygous for a G-to-A variation at position 292 of the HSP60 cDNA, resulting in the substitution of a valine at position 72 in the mature HSP60 by isoleucine (V72I; 118190.0001). Studies in E. coli indicated that the V72I mutant protein is functionally incapacitated. The authors suggested that SPG4, SPG7, and SPG13 can be referred to as chaperonopathies.
Hansen et al. (2007) screened 23 unrelated Danish patients with SPG for mutations in HSPD1 and identified 1 patient who was heterozygous for a missense mutation in the HSPD1 gene (Q461E; 118190.0003). The patient had onset of symptoms at age 52 years. Her 2 brothers, aged 56 and 65, also carried the mutation, but had no manifestations of SPG. However, their deceased mother had a gait disturbance similar to that in the proband, suggesting reduced penetrance of the mutation. The mutation was absent in 400 unrelated Danish control individuals.
Hypomyelinating Leukodystrophy 4
By linkage studies, followed by candidate gene analysis, of a large Israeli Bedouin family with autosomal recessive hypomyelinating leukodystrophy (HLD4; 612233), Magen et al. (2008) identified a homozygous mutation in the HSPD1 gene (118190.0002). The authors suggested the designation 'MitCHAP60 disease.'
In a 2-year-old boy, born to consanguineous Syrian parents, with HLD4, Kusk et al. (2016) identified homozygosity for the HSPD1 Q461E mutation previously identified in a family by Magen et al. (2008). Kusk et al. (2016) noted that the families could be distantly related.
The article by Zanin-Zhorov et al. (2006), in which it was concluded that HSP60 can downregulate adaptive immune responses by upregulating Tregs through TLR2 signaling, was retracted at the request of the authors because they had been made aware of duplicated bands in one of their figures as well as reuse of portions of another figure in a different publication.
This variant, formerly designated VAL72ILE, is here designated VAL98ILE (V98I) based on NM_199440.1.
In affected members of a French family with autosomal dominant spastic paraplegia mapping to 2q33.1 (SPG13; 605280), previously reported by Fontaine et al. (2000), Hansen et al. (2002) identified a heterozygous 292G-A transition in the HSPD1 gene, resulting in the substitution of a valine residue at position 72 with isoleucine (V72I). The mutation segregated with the disorder in the family. Studies in E. coli indicated that the V72I mutant protein is functionally incapacitated.
In 10 affected members of a consanguineous Israeli Bedouin family with autosomal recessive hypomyelinating leukodystrophy (HLD4; 612233), Magen et al. (2008) identified homozygosity for a transition in exon 2 of the HSPD1 gene (g.1512A-G), resulting in an asp29-to-gly (D29G) substitution in a highly conserved residue adjacent to the first 26 N-terminal residues composing the mitochondrial matrix targeting sequence. In vitro functional expression studies showed that transfection with the mutant protein impaired cell growth that worsened with increasing temperature. Common clinical features included infantile-onset rotary nystagmus, progressive spastic paraplegia, neurologic regression, motor impairment, profound mental retardation, and hypomyelinating leukodystrophy. Death usually occurred within the first 2 decades of life. Heterozygous carriers were unaffected.
Kusk et al. (2016) identified homozygosity for the D29G mutation in the HSPD1 gene in a 2-year-old boy, born to consanguineous Syrian parents, with HLD4. Kusk et al. (2016) noted that this family could be distantly related to the family reported by Magen et al. (2008).
In a Danish woman with spastic paraplegia-13 (SPG13; 605280), Hansen et al. (2007) identified heterozygosity for a missense mutation in the HSPD1 gene (Q461E; 118190.0003). The patient had onset of symptoms at age 52 years. Her 2 brothers, aged 56 and 65, also carried the mutation, but had no manifestations of SPG. However, their deceased mother had a gait disturbance similar to that in the proband, suggesting reduced penetrance of the mutation. The mutation was absent in 400 unrelated Danish control individuals. Functional studies in E. coli suggested that the mutation results in mild compromise of the HSP60 protein.
Azem, A., Kessel, M., Goloubinoff, P. Characterization of a functional GroEL-14(GroES-7)-2 chaperonin hetero-oligomer. Science 265: 653-656, 1994. [PubMed: 7913553] [Full Text: https://doi.org/10.1126/science.7913553]
Cheng, M. Y., Hartl, F.-U., Martin, J., Pollock, R. A., Kalousek, F., Neupert, W., Hallberg, E. M., Hallberg, R. L., Horwich, A. L. Mitochondrial heat-shock protein hsp60 is essential for assembly of proteins imported into yeast mitochondria. Nature 337: 620-625, 1989. [PubMed: 2645524] [Full Text: https://doi.org/10.1038/337620a0]
Ellis, R. J. The molecular chaperone concept. Semin. Cell Biol. 1: 1-9, 1990. [PubMed: 1983265]
Fontaine, B., Davoine, C.-S., Durr, A., Paternotte, C., Feki, I., Weissenbach, J., Hazan, J., Brice, A. A new locus for autosomal dominant pure spastic paraplegia, on chromosome 2q24-q34. Am. J. Hum. Genet. 66: 702-707, 2000. [PubMed: 10677329] [Full Text: https://doi.org/10.1086/302776]
Hansen, J. J., Bross, P., Westergaard, M., Nielsen, M. N., Eiberg, H., Borglum, A. D., Mogensen, J., Kristiansen, K., Bolund, L., Gregersen, N. Genomic structure of the human mitochondrial chaperonin genes: HSP60 and HSP10 are localised head to head on chromosome 2 separated by a bidirectional promoter. Hum. Genet. 112: 71-77, 2003. Note: Erratum: Hum. Genet. 112: 436 only, 2003. [PubMed: 12483302] [Full Text: https://doi.org/10.1007/s00439-002-0837-9]
Hansen, J. J., Durr, A., Cournu-Rebeix, I., Georgopoulos, C., Ang, D., Nielsen, M. N., Davoine, C.-S., Brice, A., Fontaine, B., Gregersen, N., Bross, P. Hereditary spastic paraplegia SPG13 is associated with a mutation in the gene encoding the mitochondrial chaperonin Hsp60. Am. J. Hum. Genet. 70: 1328-1332, 2002. [PubMed: 11898127] [Full Text: https://doi.org/10.1086/339935]
Hansen, J., Svenstrup, K., Ang, D., Nielsen, M. N., Christensen, J. H., Gregersen, N., Nielsen, J. E., Georgopoulos, C., Bross, P. A novel mutation in the HSPD1 gene in a patient with hereditary spastic paraplegia. J. Neurol. 254: 897-900, 2007. [PubMed: 17420924] [Full Text: https://doi.org/10.1007/s00415-006-0470-y]
Kusk, M. S., Damgaard, B., Risom, L., Hansen, B., Ostergaard E. Hypomyelinating leukodystrophy due to HSPD1 mutations: a new patient. Neuropediatrics 47: 332-335, 2016. [PubMed: 27405012] [Full Text: https://doi.org/10.1055/s-0036-1584564]
Magen, D., Georgopoulos, C., Bross, P., Ang, D., Segev, Y., Goldsher, D., Nemirovski, A., Shahar, E., Ravid, S., Luder, A., Heno, B., Gershoni-Baruch, R., Skorecki, K., Mandel, H. Mitochondrial Hsp60 chaperonopathy causes an autosomal-recessive neurodegenerative disorder linked to brain hypomyelination and leukodystrophy. Am. J. Hum. Genet. 83: 30-42, 2008. [PubMed: 18571143] [Full Text: https://doi.org/10.1016/j.ajhg.2008.05.016]
Rothman, J. E. Polypeptide chain binding proteins: catalysts of protein folding and related processes in cells. Cell 59: 591-601, 1989. [PubMed: 2573430] [Full Text: https://doi.org/10.1016/0092-8674(89)90005-6]
Saibil, H., Dong, Z., Wood, S., auf der Mauer, A. Binding of chaperonins. Nature 353: 25-26, 1991. [PubMed: 1679197] [Full Text: https://doi.org/10.1038/353025b0]
Schmidt, M., Rutkat, K., Rachel, R., Pfeifer, G., Jaenicke, R., Viitanen, P., Lorimer, G., Buchner, J. Symmetric complexes of GroE chaperonins as part of the functional cycle. Science 265: 656-659, 1994. [PubMed: 7913554] [Full Text: https://doi.org/10.1126/science.7913554]
Todd, M. J., Viitanen, P. V., Lorimer, G. H. Dynamics of the chaperonin ATPase cycle: implications for facilitated protein folding. Science 265: 659-666, 1994. [PubMed: 7913555] [Full Text: https://doi.org/10.1126/science.7913555]
Tokuriki, N., Tawfik, D. S. Chaperonin overexpression promotes genetic variation and enzyme evolution. Nature 459: 668-673, 2009. [PubMed: 19494908] [Full Text: https://doi.org/10.1038/nature08009]
Venner, T. J., Singh, B., Gupta, R. S. Nucleotide sequences and novel structural features of human and Chinese hamster hsp60 (chaperonin) gene families. DNA Cell Biol. 9: 545-552, 1990. [PubMed: 1980192] [Full Text: https://doi.org/10.1089/dna.1990.9.545]
Zal, B., Kaski, J. C., Arno, G., Akiyu, J. P., Xu, Q., Cole, D., Whelan, M., Russell, N., Madrigal, J. A., Dodi, I. A., Baboonian, C. Heat-shock protein 60-reactive CD4+CD28-null T cells in patients with acute coronary syndromes. Circulation 109: 1230-1235, 2004. [PubMed: 14993140] [Full Text: https://doi.org/10.1161/01.CIR.0000118476.29352.2A]
Zanin-Zhorov, A., Cahalon, L., Tal, G., Margalit, R., Lider, O., Cohen, I. R. Heat shock protein 60 enhances CD4+CD25+ regulatory T cell function via innate TLR2 signaling. J. Clin. Invest. 116: 2022-2032, 2006. Note: Retraction: J. Clin. Invest. 128: 2651 only, 2018. [PubMed: 16767222] [Full Text: https://doi.org/10.1172/JCI28423]