Alternative titles; symbols
HGNC Approved Gene Symbol: HSPB1
SNOMEDCT: 719510006;
Cytogenetic location: 7q11.23 Genomic coordinates (GRCh38): 7:76,302,673-76,304,292 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q11.23 | Charcot-Marie-Tooth disease, axonal, type 2F | 606595 | Autosomal dominant | 3 |
| Neuronopathy, distal hereditary motor, autosomal dominant 3 | 608634 | Autosomal dominant | 3 |
The heat-shock proteins (HSPs) belong to a larger group of polypeptides, the stress proteins, that are induced in various combinations in response to environmental challenges and developmental transitions. Synthesis of the small (27-kD) HSP has been shown to be correlated with the acquisition of thermotolerance. Hickey et al. (1986) cloned a HeLa cell cDNA encoding HSP27. By screening a human genomic library with this HSP27 cDNA, Hickey et al. (1986) isolated the HSP27 genomic sequence. The deduced 199-amino acid HSP27 protein shows sequence similarity to mammalian alpha-crystallins (e.g., 123580). Approximately 20% of its residues are susceptible to phosphorylation. The HSP27 gene produced a 2.2-kb transcript in an in vitro transcription assay.
Carper et al. (1990) cloned an HSP27 cDNA derived from heat-shocked human A549 lung carcinoma cells. The cDNA encodes a deduced 205-amino acid protein whose first 193 amino acids are identical to those of the predicted HSP27 protein reported by Hickey et al. (1986). Carper et al. (1990) suggested that the C-terminal differences of these deduced HSP27 proteins may be a result of a DNA sequencing artifact.
PSEUDOGENES
Hickey et al. (1986) identified a processed HSP27 pseudogene.
Hickey et al. (1986) determined that the HSP27 gene has 3 exons.
Hunt et al. (1997) mapped the mouse Hsp25 gene to chromosome 5 in a region homologous to 7q in the human. They also mapped the mouse Hsp105 gene to chromosome 5 but suggested that the human homolog is probably on 13q, not chromosome 7.
Stock et al. (2003) used FISH to map the HSP27 gene to 7q11.23. This band also contains the site of the deletion associated with Williams syndrome (194050). Stock et al. (2003) used 2-color FISH on previously G-banded and photographed metaphase chromosomes from Williams syndrome cell lines and peripheral blood. In 6 Williams syndrome patients with longer deletions that extended telomeric to the classic Williams syndrome deletion region, they found that HSP27 was telomeric to several markers and was deleted in 3. They discussed the possible role of HSP27 in the cognitive features of Williams syndrome.
New et al. (1998) demonstrated that MAPKAPK5 (606723) is a major stress-activated kinase that can phosphorylate HSP27 in vitro.
Using a cellular model of Huntington disease (143100), Wyttenbach et al. (2002) identified HSP27 as a suppressor of polyglutamine (polyQ)-mediated cell death. In contrast to HSP40 (see 604572) and HSP70 (see 140550) chaperones, HSP27 suppressed polyQ death without suppressing polyQ aggregation. While polyQ-induced cell death was reduced by inhibiting cytochrome c release from mitochondria, protection by HSP27 was regulated by its phosphorylation status and was independent of its ability to bind to cytochrome c. However, mutant huntingtin (HTT; 613004) caused increased levels of reactive oxygen species (ROS) in neuronal and nonneuronal cells. ROS contributed to cell death because both N-acetyl-L-cysteine and glutathione in its reduced form suppressed polyQ-mediated cell death. HSP27 decreased ROS in cells expressing mutant huntingtin, suggesting that this chaperone may protect cells against oxidative stress. The authors proposed that a polyQ mutation may induce ROS that directly contribute to cell death, and that HSP27 may be an antagonist of this process.
The alpha-crystallin subunits alpha-A (123580) and alpha-B (123590) each can form an oligomer by itself or with the other. Fu and Liang (2002) used a 2-hybrid system to study heterogeneous interactions among lens crystallins of different classes. They found interactions between alpha-A- (or alpha-B-) and beta-B2- (123620) or gamma-C-(123680) crystallins, but the intensity of interaction was one-third that of alpha-A-alpha-B interactions. HSP27 showed similar interaction properties with alpha-B-crystallin. Experiments with N- and C-terminal domain-truncated mutants demonstrated that both N- and C-terminal domains were important in alpha-A-crystallin self-interaction, but that only the C-terminal domain was important in alpha-B-crystallin self-interaction.
When fed a diet supplemented with cholesterol, Apoe (107741) -/- mice develop inflammatory atherosclerosis. Rayner et al. (2008) found that overexpression of human HSP27 reduced atherosclerotic lesions in aortic arches excised from Apoe -/- female mice by 35% compared with Apoe -/- controls. HSP27 overexpression had no effect on atherosclerotic lesions in Apoe -/- male mice. However, there was an inverse correlation between serum HSP27 level and atherosclerotic lesion area in both male and female Apoe -/- mice. HSP27 was secreted from cultured human macrophages in response to estrogen and acetylated low density lipoprotein (acLDL). Extracellular HSP27 bound the scavenger receptor SRA (MSR1; 153622) on murine macrophages and prevented acLDL uptake. Extracellular HSP27 also decreased acLDL-induced release of the proinflammatory cytokine Il1b (147720) and increased the release of the antiinflammatory cytokine Il10 (124092) by mouse macrophages. Overexpression of HSP27 in Apoe -/- mouse macrophages reduced their adherence and migration in vitro. Rayner et al. (2008) concluded that HSP27 is atheroprotective, possibly by competing for uptake of atherogenic lipids by macrophages or by attenuating inflammation.
De Thonel et al. (2010) stated that HSP27 is a ubiquitin-binding protein involved in proteasomal degradation of certain proteins under stress conditions. They found that HSP27 was involved in proteasome-mediated degradation of GATA1 (305371), a transcription factor that directs erythroblast proliferation, but not differentiation. Knockdown of HSP27 or overexpression of GATA1 inhibited differentiation of primary cultured human erythroid cells and the K562 erythroleukemia cell line. HSP27-mediated GATA1 degradation was reduced by proteasome inhibitors and required prior acetylation of GATA1 and serine phosphorylation of HSP27 via the p38 MAP kinase (MAPK14; 600289) pathway.
Axonal Charcot-Marie-Tooth Disease Type 2F
In affected members of 2 families with axonal Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) and in affected members of 4 families with distal hereditary motor neuropathy (HMN2B; 608634), Evgrafov et al. (2004) identified heterozygous mutations in the HSPB1 gene (602195.0001-602195.0004).
Distal Hereditary Motor Neuronopathy 3, Autosomal Dominant
Houlden et al. (2008) identified 4 different heterozygous mutations in the HSPB1 gene (see, e.g., 602195.0001; 602195.0007) in affected members of 4 of 25 families with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634). An additional patient with autosomal recessive inheritance was found to have a homozygous mutation (602195.0008). All patients had a predominant motor neuropathy without clinical sensory abnormalities. No HSPB1 mutations were found in 90 families with CMT2.
Variant Function
Benndorf and Welsh (2004) reviewed the role of heat-shock proteins in neuromuscular function, as indicated by the association of mutations in 2 of these genes, HSP22 (608014) and HSP27, with human neuromuscular disorders.
D'Ydewalle et al. (2011) demonstrated that transgenic mice expressing the S135F (602195.0001) or P182L (602195.0004) Hspb1 mutations developed clinical and pathologic features of axonal CMT or distal HMN. Mutant mice developed progressive motor impairment, decreased muscle strength, and clawed hindpaws, features that were more apparent in P182L mice, as P182L is associated with the dHMN phenotype. S135F mutants showed sensory abnormalities, whereas P182L mutant mice did not. Sensory loss in the S135F mutants was associated with decreased sensory amplitudes on electrophysiologic studies and impaired mitochondrial axonal transport in dorsal root ganglion cells. Both mouse mutants showed distal axonal loss on nerve biopsy, and both had a decrease in acetylated alpha-tubulin (TUBA1A; 602529) in peripheral nerves. Treatment of S135F mutant mice with an HDAC6 (300272) inhibitor resulted in restoration of axonal transport and partial reversal of the CMT phenotype.
In affected members of a Russian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595) previously reported by Ismailov et al. (2001), Evgrafov et al. (2004) identified a heterozygous c.404C-T transition in exon 2 of the HSPB1 gene, resulting in a ser135-to-phe (S135F) substitution. In affected members of an unrelated family from the United Kingdom with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), the authors identified the same mutation in heterozygosity. The S135F mutation occurs in a highly conserved alpha-crystallin domain of the protein. In vitro expression of the mutant protein resulted in reduced viability of neuronal cells and impaired neurofilament assembly. Evgrafov et al. (2004) suggested that these deficits may be responsible for premature axonal degeneration, which underlies both CMT and dHMN.
Houlden et al. (2008) identified a heterozygous S135F mutation in affected members of a large family with HMND3. The mean age at onset was 21 years, and sensory abnormalities were not present.
Variant Function
In cultured mouse motor neurons, Zhai et al. (2007) showed that expression of S135F-mutant HSPB1 led to progressive degeneration of motor neurons with disruption of the neurofilament network and aggregation of NEFL (162280) protein. The 2 proteins were found to associate together, and the S135F mutant had a dominant effect. Similarly, expression of NEFL mutants (e.g., 162280.0003) also led to disruption of the neurofilament network and aggregation of NEFL, and wildtype HSPB1 induced reversal of NEFL aggregates. Zhai et al. (2007) suggested that disruption of the neurofilament network with aggregation of NEFL is a common triggering event of motor neuron degeneration in CMT2E (607684) and CMT2F.
In affected members of a Belgian family with autosomal dominant distal hereditary motor neuronopathy 3 (HMND3; 608634), Evgrafov et al. (2004) identified a heterozygous c.379C-T transition in exon 2 of the HSPB1 gene, resulting in an arg127-to-trp (R127W) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein.
In affected members of 4 Chinese Han families with late-onset Charcot-Marie-Tooth disease type 2F (CMT2F; 606595), Tang et al. (2005) identified heterozygosity for the R127W substitution. Haplotype analysis indicated a founder effect. Three mutation carriers from different families, ranging in age from 23 to 37 years, were asymptomatic, possibly reflecting age-dependent penetrance.
In affected members of a Croatian family with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Evgrafov et al. (2004) identified a heterozygous c.452C-T transition in exon 2 of the HSPB1 gene, resulting in a thr151-to-ile (T151I) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein.
In affected members of an Austrian family with autosomal dominant distal hereditary motor neuropathy-3 (HMND3; 608634), Evgrafov et al. (2004) identified a heterozygous c.545C-T transition in exon 3 of the HSPB1 gene, resulting in a pro182-to-leu (P182L) substitution. The mutation occurs in the variable C-terminal tail of the protein.
Variant Function
By in vitro functional expression studies, Ackerley et al. (2006) showed that in mouse primary cortical cells the P182L-mutant protein formed aggregates and failed to be transported down neuronal processes unlike the wildtype protein. Coexpression of the mutant and wildtype protein resulted in sequestration of the wildtype protein into mutant aggregates. Mutant HSPB1 also disrupted the formation of intracellular neurofilaments and disrupted the transport of specific cellular cargoes, such as the p150 dynactin (DCTN1; 601143), but not mitochondria.
In affected members of a Belgian family with Charcot-Marie-Tooth disease type 2F (CMT2F; 606595), Evgrafov et al. (2004) identified a heterozygous c.406C-T transition in exon 2 of the HSPB1 gene, resulting in an arg136-to-trp (R136W) substitution. The mutation occurs in a highly conserved alpha-crystallin domain of the protein.
In a Japanese patient with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Kijima et al. (2005) identified heterozygosity for a c.544C-T transition in exon 3 of the HSBP1 gene, resulting in a pro182-to-ser (P182S) substitution. The mutation was not detected in his parents or older brother or in 100 control chromosomes.
In affected individuals from an Indian family with autosomal dominant distal hereditary motor neuronopathy-3 (HMND3; 608634), Houlden et al. (2008) identified a heterozygous c.418C-G transversion in exon 2 of the HSPB1 gene, resulting in an arg140-to-gly (R140G) substitution in the alpha-crystallin domain. The mean age of onset in this family was 29 years, and both father and son had distal motor neuropathy without sensory abnormalities. Two additional Indian patients with sporadic HMN2B were also found to carry the R140G mutation.
In a Pakistani patient, born of consanguineous parents, with distal HMN2B (608634), Houlden et al. (2008) identified a homozygous 295C-A transversion in exon 1 of the HSPB1 gene, resulting in a leu99-to-met (L99M) substitution in the alpha-crystallin domain. He had onset at age 37 years of difficulty walking, and had distal muscle weakness and atrophy without sensory involvement. The patient's unaffected mother and sister were heterozygous for the mutation, suggesting that it may act in a dose-dependent fashion. This was the first report of autosomal recessive inheritance of HSPB1 mutations. The mutation occurred in a conserved residue and was not found in 220 controls.
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Benndorf, R., Welsh, M. J. Shocking degeneration. Nature Genet. 36: 547-548, 2004. [PubMed: 15167925] [Full Text: https://doi.org/10.1038/ng0604-547]
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de Thonel, A., Vandekerckhove, J., Lanneau, D., Selvakumar, S., Courtois, G., Hazoume, A., Brunet, M., Maurel, S., Hammann, A., Ribeil, J. A., Zermati, Y., Gabet, A. S., Boyes, J., Solary, E., Hermine, O., Garrido, C. HSP27 controls GATA-1 protein level during erythroid cell differentiation. Blood 116: 85-96, 2010. [PubMed: 20410505] [Full Text: https://doi.org/10.1182/blood-2009-09-241778]
Evgrafov, O. V., Mersiyanova, I., Irobi, J., Van Den Bosch, L., Dierick, I., Leung, C. L., Schagina, O., Verpoorten, N., Van Impe, K., Fedotov, V., Dadali, E., Auer-Grumbach, M., and 14 others. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nature Genet. 36: 602-606, 2004. [PubMed: 15122254] [Full Text: https://doi.org/10.1038/ng1354]
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Zhai, J., Lin, H., Julien, J.-P., Schlaepfer, W. W. Disruption of neurofilament network with aggregation of light neurofilament protein: a common pathway leading to motor neuron degeneration due to Charcot-Marie-Tooth disease-linked mutations in NFL and HSPB1. Hum. Molec. Genet. 16: 3103-3116, 2007. [PubMed: 17881652] [Full Text: https://doi.org/10.1093/hmg/ddm272]