Alternative titles; symbols
HGNC Approved Gene Symbol: HSPB8
Cytogenetic location: 12q24.23 Genomic coordinates (GRCh38) : 12:119,178,931-119,194,746 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q24.23 | Charcot-Marie-Tooth disease, axonal, type 2L | 608673 | Autosomal dominant | 3 |
| Myopathy, myofibrillar, 13, with rimmed vacuoles | 621078 | Autosomal dominant | 3 | |
| Neuronopathy, distal hereditary motor, autosomal dominant 2 | 158590 | Autosomal dominant | 3 |
The HSPB8 gene encodes a molecular chaperone that is a component of the chaperone-assisted selective autophagy (CASA) complex, which is is involved in the recognition and removal of misfolded and aggregated cellular proteins through ubiquitination and autophagic degradation. HSPB8 works in conjunction with BAG3 (603883), STUB1 (607207), and HSPA1A (HSP72; 140550) in the CASA complex. In muscle, CASA promotes the turnover of structural components damaged by mechanical stress, and in neurons, CASA functions in the removal of misfolded substrates implicated in neurodegenerative diseases (summary by Tedesco et al., 2023, Yang et al., 2025).
To identify genes that are regulated by or associated with estrogen action, Charpentier et al. (2000) performed serial analysis of gene expression (SAGE) on estrogen-responsive breast cancer cells after exposure to estrogen. Using transcript-specific PCR primers for novel sequences that increased more than 10-fold upon treatment with 17-beta estradiol (E2), they cloned 5 cDNAs, designated E2-induced genes (E2IG) 1-5, from a human placenta cDNA library. The E2IG1 cDNA encodes a deduced 196-amino acid protein that contains a central portion homologous to a highly conserved HSP-alpha crystallin domain common to all HSP20 family members. It shows 54% sequence homology to HSP27 (602195), suggesting that it is a member of the small HSP family.
By searching an EST database for sequences containing the alpha-crystallin domain characteristic of small heat-shock proteins, followed by PCR of a placenta cDNA library, Kappe et al. (2001) cloned HSPB8. Northern blot analysis detected broad expression of a 2.2-kb transcript, with highest abundance in skeletal muscle, heart, and placenta. Expression of HSPB8 was intermediate in several other tissues, but it was not detected in blood.
Kappe et al. (2001) determined that the HSPB8 gene contains at least 3 exons.
By sequence analysis, Charpentier et al. (2000) mapped the E2IG1 gene to chromosome 12 between markers D12S366 and D12S340.
Carra et al. (2005) investigated the capacity of HSPB8 to prevent protein aggregation in cells using Htt (613004) protein containing 43 glutamine residues (Htt43Q) as a model. In control conditions, Htt43Q accumulated in perinuclear inclusions composed of SDS-insoluble aggregates. In most cells, cotransfection with HSPB8 blocked inclusion formation. Biochemical analyses indicated that HSPB8 inhibited the accumulation of insoluble Htt43Q as efficiently as HSP40 (DNAJB1; 604572), which was taken as a positive control. Htt43Q then accumulated in the SDS-soluble fraction, provided that protein degradation was blocked by proteasome and autophagy inhibitors. In contrast, HSPB1 (602195) and alpha-B-crystallin (CRYAB; 123590) had no effect. Analyses of HSPB1/HSPB8 chimeric proteins indicated that the C-terminal domain of HSPB8 contains the specific sequence necessary for chaperone activity. The K141N mutation (608014.0001) significantly reduced the chaperone activity of the protein. Carra et al. (2005) hypothesized that a decrease in HSPB8 chaperone activity may contribute to the development of some neuropathies.
Abdel-Nour et al. (2019) found that the EIF2-alpha (603907) kinase heme-regulated inhibitor (HRI; 613635) controls NOD1 (605980) signalosome folding and activation through a process requiring eIF2-alpha, the transcription factor ATF4 (604064), and the heat-shock protein HSPB8. The HRI/eIF2-alpha signaling axis was also essential for signaling downstream of the innate immune mediators NOD2 (605956), MAVS (609676), and TRIF (607601) but dispensable for pathways dependent on MyD88 (602170) or STING (612374). Moreover, filament-forming alpha-synuclein (163890) activated HRI-dependent responses, which suggested that the HRI pathway may restrict toxic oligomer formation. Abdel-Nour et al. (2019) proposed that HRI, eIF2-alpha, and HSPB8 define a novel cytosolic unfolded protein response (cUPR) essential for optimal innate immune signaling by large molecular platforms, functionally homologous to the PERK (EIF2AK3; 604032)/eIF2-alpha/HSPA5 (138120) axis of the endoplasmic reticulum (ER) unfolded protein response.
Reviews
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 and HSP27, with human neuromuscular disorders.
Distal Hereditary Motor Neuronopathy Type IIA
In affected members of 4 families with autosomal dominant distal hereditary motor neuronopathy type IIA (dHMN2A; 158590), Irobi et al. (2004) identified heterozygous missense mutations in the same codon of the HSPB8 gene (K141N, 608014.0001 and K141E, 608014.0002). The K141N substitution resulted from a c.423G-C transversion. Expression studies of the mutant proteins in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. Of note, Tang et al. (2005) identified a K141N mutation resulting from a c.423G-T transversion (608014.0003) in affected members of a Chinese family with Charcot-Marie-Tooth disease type 2L (608673).
In a woman and her 2 children (family 1) with HMND2 and later onset of myofibrillar myopathy, Ghaoui et al. (2016) identified a heterozygous missense mutation in the HSPB8 gene (K141E; 608014.0002). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Segregation studies indicated that the mutation occurred de novo in the mother. In vitro studies showed that the mutant K141E protein lost its ability to prevent abnormal protein aggregation.
Irobi et al. (2010) compared the effect of mutant HSPB8 in primary neuronal and glial cell cultures of rat and mouse cells. In rat motor neurons, expression of both HSPB8 K141N (608014.0001) and K141E (608014.0002) mutations resulted in neurite degeneration, as manifested by a reduction in number of neurites per cell, as well as in a reduction in average length of the neurites. Expression of the K141E, and to a lesser extent the K141N, mutation also induced spheroids in the neurites. There were no signs of apoptosis in motor neurons, showing that mutant HSPB8 resulted in neurite degeneration without inducing neuronal death. While overt in rat motor neurons, these phenotypes were only very mildly present in embryonic mouse sensory neurons and completely absent in embryonic mouse cortical neurons and glial cells.
Irobi et al. (2012) found that cultured fibroblasts derived from 2 patients with the K141N mutation (608014.0001) showed transient HSPB8-positive intracellular protein aggregates. Early passages had small aggregates, whereas later passages had fewer and larger aggregates that decreased over time due to activation of the ubiquitin proteosomal removal process. Mitochondrial membrane potential was reduced in early passage mutant fibroblasts, although mitochondrial morphology was normal, and the mitochondrial potential was restored with time. There was no significant evidence of apoptosis. Electron microscopy showed decreased numbers of myelinated and unmyelinated sensory axons with mild axonal abnormalities. The authors noted the drawbacks in using nonneuronal cells to study neuropathologic disease mechanisms, and suggested that studies of motor neurons or reprogrammed iPS cell-derived motor neurons would be more informative for studying this disease.
Axonal Charcot-Marie-Tooth Disease Type 2L
In affected members of a Chinese family with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; 608673), Tang et al. (2005) identified a heterozygous K141N missense mutation in the HSPB8 gene (608014.0003), resulting from a c.423G-T transversion. No functional studies were performed. Of note, Irobi et al. (2004) identified a K141N mutation resulting from a c.423G-C transversion (608014.0001) in affected members of 2 families with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590).
In a 27-year-old Korean man, born of unrelated parents, with CMT2L, Nakhro et al. (2013) identified a de novo heterozygous K141T mutation in the HSPB8 gene (608014.0009). The mutation, which was found by exome sequencing, was not present in public databases. Functional studies of the variant were not performed.
Myofibrillar Myopathy-13 With Rimmed Vacuoles
In 2 affected members of a French Caucasian family (family 2) with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Ghaoui et al. (2016) identified a heterozygous frameshift mutation in the last exon of the HSPB8 gene (608014.0004), predicted to result in a frameshift and extension of the protein by 18 amino acids (Pro173SerfsTer43). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The proband also carried a heterozygous missense variant (K238E) in the SQSTM1 gene (601530), but his affected cousin did not carry that variant. Functional studies of the variants were not performed.
In 3 members of a French family with MFM13, Al-Tahan et al. (2019) identified a heterozygous frameshift mutation in the HSPB8 gene (608014.0004), the same mutation reported by Ghaoui et al. (2016). The mutation, which was found by whole-genome sequencing, was not present in gnomAD. Western blot analysis of patient fibroblasts showed a 50% reduction of the HSPB8 protein. There was increased expression of autophagosomal markers LC3B (609604) and SQSTM1. Patient fibroblasts had excessive amounts of HSPB8 protein aggregates in response to heat shock compared to controls.
In 6 patients from 3 unrelated families with MFM13, Echaniz-Laguna et al. (2017) identified a heterozygous frameshift mutation in the HSPB8 gene (608014.0005) and extension of the protein by 17 amino acids (Gln170GlyfsTer45). The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in families A and B; the patient in family C was a sporadic case. The mutation was not present in gnomAD. Western blot analysis of cells from 1 patient showed that HSPB8 protein levels were reduced by 60%. Neither an elongated nor a truncated HSPB8 protein was identified using an antibody to the N-terminal region, suggesting to the authors that the mutation induces nonsense-mediated mRNA decay or protein degradation and may result in HSPB8 haploinsufficiency. The patients presented with adult-onset axial and distal myopathy without evidence of a neuropathy.
In a 23-year-old man with MFM13 manifest as proximal limb-girdle muscle weakness, Nicolau et al. (2020) identified a de novo heterozygous frameshift mutation in the C-terminal region of the HSPB8 gene (Thr194SerfsTer23; 608014.0006) that resulted in extension of the protein. The mutation, which was found by whole-exome sequencing, was not present in gnomAD. Functional studies of the variant were not performed.
In 6 affected members of a multigenerational Japanese family with MFM13, Inoue-Shibui et al. (2021) identified a heterozygous frameshift mutation in the C terminus of the HSPB8 gene (608014.0007), predicted to result in a frameshift and elongation of the protein (Thr176TrpfsTer38). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but these authors suggested that the mutant transcript would escape nonsense-mediated mRNA decay.
In an 18-year-old Chinese girl with MFM13, Yang et al. (2025) identified a de novo heterozygous frameshift mutation in the C terminus of the HSPB8 gene (608014.0008), resulting in a frameshift and extension of the protein by 49 amino acids (Glu192AspfsTer55). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Direct functional studies of the variant were not performed, but patient muscle biopsy showed accumulation of autophagy molecules. The authors concluded that the mutant transcript likely evaded nonsense-mediated mRNA decay, and suggested that it may result in a toxic gain of function, likely leading to dysregulation of autophagy. The patient had onset of axial and limb-girdle myopathy at 6 years of age. She did not have sensory involvement.
Tedesco et al. (2023) found that different mutations affecting the C terminus of HSPB8 associated with MFM13 resulted in an identical carboxy-terminal extension of the protein and that the added amino acid sequence is prone to aggregation. Detailed in vitro studies of 3 HSPB8 C-terminal frameshift mutations, P173SfsX43 (608014.0004), T194SfsX23 (608014.0006), and Q170GfsX45 (608014.0005), in HeLa cells, human myoblasts, murine NSC34 neuroblastoma cells, and HEK293 cells showed that the mutant proteins interacted with other CASA subunits (wildtype HSPB8, BAG3, HSPA1A, and STUB1) and formed highly insoluble cytoplasmic aggregate structures that contained ubiquitinated CASA substrates, suggesting disruption of HSPB8 autophagy chaperone function. The abnormal aggregates were associated with 2 autophagy receptors SQSTM1/p62 and TAX1BP1 (605326). Human myoblasts expressing the frameshift mutations showed impaired differentiation and disorganization of the sarcomere structure. The overall findings were consistent a toxic gain-of-function effect of these mutations, ultimately resulting in a general failure of proteostasis affecting muscle cells. The authors noted that haploinsufficiency had previously been suggested as the pathomechanism of C-terminal mutations, but that their findings confirmed a dominant toxic gain-of-function effect.
Dominantly inherited HSPB8 mutations affecting the conserved lysine-141 residue (K141) are found in patients with motor neuropathy (HMND2; 158590) or sensorimotor neuropathy (CMT2L; 608673), whereas dominant or de novo frameshift mutations at the HSPB8 C terminus, resulting in elongated proteins, are predominantly associated with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078) (Tedesco et al., 2023).
In affected members of a Belgian family with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590), previously reported by Timmerman et al. (1992), and in affected members of a large Czech family with HMND2, Irobi et al. (2004) identified a heterozygous c.423G-C transversion in exon 2 of the HSPB8 gene, resulting in a lys141-to-asn (K141N) substitution. The mutation cosegregated with the disease in both families. The K141N mutation affects a highly conserved residue in the central alpha-crystallin domain of the protein. Normally, HSPB8 interacts with HSPB1 (602195). Expression studies of the K141N mutant protein in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. Of note, Tang et al. (2005) identified a K141N mutation resulting from a c.423G-T transversion (608014.0003) in affected members of a Chinese family with Charcot-Marie-Tooth disease type 2L (CMT2L; 608673).
In affected members of an English family and a Bulgarian family with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590), Irobi et al. (2004) identified a heterozygous c.421A-G transition in exon 2 of the HSPB8 gene, resulting in a lys141-to-glu (K141E) substitution. The mutation cosegregated with the disease in both families. The K141E mutation affects a highly conserved residue in the central alpha-crystallin domain of the protein. Normally, HSPB8 interacts with HSPB1 (602195). Expression studies of the mutant K141E protein in COS cells showed an increased interaction between HSPB8 and HSPB1, leading to the formation of intracellular aggregates. A different mutation in the same codon was identified in 2 other families with HMND2 (608014.0001).
In a woman and her 2 children (family 1) with HMND2 and later onset of myofibrillar myopathy, Ghaoui et al. (2016) identified a heterozygous c.421A-G transition (c.421A-G, NM_014365) in the HSPB8 gene, resulting in a lys141-to-glu (K141E) substitution. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Segregation studies indicated that the mutation occurred de novo in the mother. In vitro studies showed that the mutant K141E protein lost its ability to prevent abnormal protein aggregation.
In a mother and her trizygotic triplets with young adult onset of a hereditary motor neuropathy and myofibrillar myopathy, Cortese et al. (2018) identified a heterozygous K141E mutation in the HSPB8 gene. Studies of muscle biopsy from 1 patient showed decreased mRNA levels of TDP43 (605078), which was associated with abnormal splicing of TDP43 substrates. Of note, the mother and 1 of the triplets also carried a heterozygous missense variant of unknown significance (H248R) in the BAG3 gene (603883). The findings confirmed that mutant HSPB8 can cause a combined neuromuscular disorder exhibiting both motor neuropathy and myofibrillar myopathy.
In affected members of a large Chinese family with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; 608673) in which Tang et al. (2004) assigned the underlying locus to 12q24, Tang et al. (2005) identified a c.423G-T transversion in exon 2 of the HSPB8 gene, resulting in a lys141-to-asn (K141N) substitution. Functional studies were not performed. Of note, Irobi et al. (2004) identified a K141N mutation resulting from a c.423G-C transversion (608014.0001) in affected members of 2 families with autosomal dominant distal hereditary motor neuronopathy-2 (HMND2; 158590).
In 2 affected members of a French Caucasian family (family 2) with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Ghaoui et al. (2016) identified a heterozygous 1-bp insertion (c.515insC, NM_014365) in the last exon of the HSPB8 gene, predicted to result in a frameshift and extension of the protein by 18 amino acids (Pro173SerfsTer43). The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The proband also carried a heterozygous missense variant (K238E) in the SQSTM1 gene (601530), but his affected cousin did not carry that variant. Functional studies of the variants were not performed.
In 3 members of a French family with MFM13, Al-Tahan et al. (2019) identified a heterozygous 1-bp duplication (c.515dupC), predicted to result in a frameshift and elongation of the HSPB8 protein (Pro173SerfsTer43), the same mutation reported by Ghaoui et al. (2016). The mutation, which was found by whole-genome sequencing, was not present in gnomAD. Western blot analysis of patient fibroblasts showed a 50% reduction of the HSPB8 protein. There was increased expression of autophagosomal markers LC3B and SQSTM1. Patient fibroblasts had excessive amounts of HSPB8 protein aggregates in response to heat shock compared to controls.
In 6 patients from 3 unrelated families with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Echaniz-Laguna et al. (2017) identified a heterozygous 2-bp deletion (c.508_509delCA, NM_014365.2) in the HSPB8 gene, predicted to result in a frameshift and extension of the protein by 17 amino acids (Gln170GlyfsTer45). The mutation, which was found by exome sequencing or targeted sequencing and confirmed by Sanger sequencing, segregated with the disorder in families A and B; the patient in family C was a sporadic case. The mutation was not present in gnomAD. Western blot analysis of cells from 1 patient showed that the HSPB8 protein levels were reduced by 60%. Neither an elongated nor a truncated HSPB8 protein was identified using an antibody to the N-terminal region, suggesting to the authors that the mutation induces nonsense-mediated mRNA decay or protein degradation and may result in HSPB8 haploinsufficiency. The patients presented with adult-onset axial and distal myopathy without evidence of a neuropathy.
In a 23-year-old man with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Nicolau et al. (2020) identified a de novo heterozygous 4-bp duplication (c.577_580dupGTCA, NM_014365) in the C-terminal region of the HSPB8 gene, predicted to result in a frameshift and elongation of the protein (Thr194SerfsTer23). The mutation, which was found by whole-exome sequencing, was not present in gnomAD. Functional studies of the variant were not performed. The phenotype was manifest as proximal limb-girdle muscle weakness.
In 6 affected members of a multigenerational Japanese family with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Inoue-Shibui et al. (2021) identified a heterozygous 5-bp deletion (c.525_529del, NM_014365.3) in the HSPB8 gene, predicted to result in a frameshift and elongation of the protein (Thr176TrpfsTer38). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed, but these authors suggested that the mutant transcript would escape nonsense-mediated mRNA decay.
In an 18-year-old Chinese girl with myofibrillar myopathy-13 with rimmed vacuoles (MFM13; 621078), Yang et al. (2025) identified a de novo heterozygous del/ins mutation (c.576_579delinsCAG, NM_014365) in the HSPB8 gene, resulting in a frameshift and extension of the protein by 49 amino acids (Glu192AspfsTer55). The mutation, which was found by whole-exome sequencing, was not present in the gnomAD database. Direct functional studies of the variant were not performed, but patient muscle biopsy showed accumulation of autophagy molecules. The authors concluded that the mutant transcript likely evaded nonsense-mediated mRNA decay, and suggested that it may result in a toxic gain of function, likely leading to dysregulation of autophagy. The patient had onset of axial and limb-girdle myopathy at 6 years of age. She did not have sensory involvement.
In a 27-year-old Korean man, born of unrelated parents, with axonal Charcot-Marie-Tooth disease type 2L (CMT2L; 608673), Nakhro et al. (2013) identified a de novo heterozygous c.422A-C transversion in the HSPB8 gene, resulting in a lys141-to-thr (K141T) substitution at a conserved residue in the alpha-crystallin domain. The mutation, which was found by exome sequencing, was not present in public databases. Functional studies of the variant were not performed.
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