HSPB8

Summary

HSPB8 (heat shock protein family B (small) member 8, HGNC:30171) is a protein-coding gene on chromosome 12q24.23, encoding Heat shock protein beta-8 (Q9UJY1). Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle.

The protein encoded by this gene belongs to the superfamily of small heat-shock proteins containing a conservative alpha-crystallin domain at the C-terminal part of the molecule. The expression of this gene in induced by estrogen in estrogen receptor-positive breast cancer cells, and this protein also functions as a chaperone in association with Bag3, a stimulator of macroautophagy. Thus, this gene appears to be involved in regulation of cell proliferation, apoptosis, and carcinogenesis, and mutations in this gene have been associated with different neuromuscular diseases, including Charcot-Marie-Tooth disease.

Source: NCBI Gene 26353 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neuronopathy, distal hereditary motor, autosomal dominant (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 282 total — 10 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 86
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_014365

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30171
Approved symbol	HSPB8
Name	heat shock protein family B (small) member 8
Location	12q24.23
Locus type	gene with protein product
Status	Approved
Aliases	H11, E2IG1, HSP22, CMT2L
Ensembl gene	ENSG00000152137
Ensembl biotype	protein_coding
OMIM	608014
Entrez	26353

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 6 protein_coding, 6 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000281938, ENST00000541798, ENST00000542496, ENST00000674542, ENST00000674715, ENST00000674763, ENST00000674852, ENST00000675110, ENST00000675211, ENST00000675573, ENST00000675900, ENST00000676008, ENST00000676071, ENST00000676244

RefSeq mRNA: 1 — MANE Select: NM_014365 NM_014365

CCDS: CCDS9189

Canonical transcript exons

ENST00000281938 — 3 exons

Exon	Start	End
ENSE00001003595	119187025	119187088
ENSE00001132445	119178931	119179679
ENSE00001209003	119193699	119194746

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 99.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.5939 / max 1439.9669, expressed in 1314 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128290	26.9211	1297
128289	1.2108	547
128292	1.2009	242
128291	0.4326	212
128288	0.3875	211
128287	0.2677	145
206924	0.1733	80

Top tissues by expression

295 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.60	gold quality
mucosa of stomach	UBERON:0001199	99.52	gold quality
gastrocnemius	UBERON:0001388	99.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.51	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.49	gold quality
lower esophagus	UBERON:0013473	99.48	gold quality
cardiac ventricle	UBERON:0002082	99.40	gold quality
heart left ventricle	UBERON:0002084	99.40	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.38	gold quality
right atrium auricular region	UBERON:0006631	99.35	gold quality
heart right ventricle	UBERON:0002080	99.32	gold quality
gluteal muscle	UBERON:0002000	99.31	gold quality
cardiac atrium	UBERON:0002081	99.30	gold quality
skeletal muscle tissue	UBERON:0001134	99.25	gold quality
apex of heart	UBERON:0002098	99.25	gold quality
body of tongue	UBERON:0011876	99.25	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.22	gold quality
vastus lateralis	UBERON:0001379	99.16	gold quality
quadriceps femoris	UBERON:0001377	99.13	gold quality
right coronary artery	UBERON:0001625	99.10	gold quality
deltoid	UBERON:0001476	99.03	gold quality
tibialis anterior	UBERON:0001385	99.01	gold quality
biceps brachii	UBERON:0001507	99.00	gold quality
heart	UBERON:0000948	98.98	gold quality
triceps brachii	UBERON:0001509	98.97	gold quality
muscle organ	UBERON:0001630	98.91	gold quality
skeletal muscle organ	UBERON:0014892	98.91	gold quality
cranial nerve II	UBERON:0000941	98.90	gold quality
lateral globus pallidus	UBERON:0002476	98.88	gold quality
pharyngeal mucosa	UBERON:0000355	98.86	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	1101.88
E-MTAB-5061	yes	27.42
E-GEOD-81547	yes	24.54
E-GEOD-135922	yes	15.28
E-MTAB-8060	no	426.57
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

54 targeting HSPB8, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-372-5P	99.41	69.11	2299
HSA-MIR-19A-5P	99.36	66.93	1675
HSA-MIR-19B-1-5P	99.36	67.07	1669
HSA-MIR-19B-2-5P	99.36	67.07	1669
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-5690	99.25	67.58	1012
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-642A-3P	99.23	67.67	1258
HSA-MIR-642B-3P	99.23	67.67	1258
HSA-MIR-3127-3P	98.94	67.34	1055
HSA-MIR-6756-3P	98.94	66.79	1104
HSA-MIR-1288-5P	98.85	67.01	734

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• This gene is highly upregulated by estradiol treatment in breast cancer cells. It is overexpressed in estrogen receptor (ER) positive breast cancer cell lines and transcript is not detected in ER negative cell lines. (PMID:11085516)
• H11 kinase is a novel mediator of myocardial hypertrophy in vivo (PMID:12456486)
• Forced H11 expression triggers apoptosis. (PMID:12832417)
• In two pedigrees with distal hereditary motor neuropathy type II linked to chromosome 12q24.3, we identified the same mutation (K141N) in small heat-shock 22-kDa protein 8 (encoded by HSPB8; also called HSP22). (PMID:15122253)
• Hsp22 is highly homologous to small heat shock proteins and effectively prevents aggregation of denatured protein both in vitro and in vivo. It is supposed that chaperone-like activity is of great importance for Hsp22 functioning (PMID:15541337)
• Reduced chaperone activity of mutated HspB8 is associated with neuromuscular disorders (PMID:15879436)
• The rate of HSP22 gene mutation in Chinese patients with Charcot-Marie-Tooth disease is as low as 0.87%(1/115). (PMID:16086267)
• Our results suggest that a variety of oligomers composed of different proportions of different sHSPs may form in cell types expressing multiple sHSPs. (PMID:16225851)
• HspB8 might play important role in regulating Abeta aggregation and, therefore, development of classic senile plaques in Alzheimer’s disease and cerebral amyloid angiopathy in hereditary cerebral hemorrhage with amyloidosis of Dutch type. (PMID:16485107)
• Small heat shock protein B8 (HSP22) is a novel TLR4 agonist abundantly expressed in synovial tissue from patients with rheumatoid arthritis. (PMID:16709864)
• Results suggest that hsp22 specifically binds to Sam68 and modulates its activity, thus playing a role in the post-transcriptional regulation of gene expression. (PMID:16795043)
• found aberrantly increased interactions of neuropathy-associated mutant HSP22 forms with themselves, with wild-type HSP22, and with the other sHSPs, alphaB-crystallin, and HSP27. (PMID:16935933)
• Aberrant DNA methylation silences the novel heat shock protein H11 in melanoma (PMID:17033167)
• HspB8 overload causes melanoma growth arrest and apoptosis through TAK1 activation (PMID:17173073)
• Displays chaperone activity, autokinase activity, and trigger or block apoptosis activity. Decrease may contribute to development of some neurologic diseases and others. (Review) (PMID:17304582)
• HSP22 seems to play an important role in the nervous system. (PMID:17722063)
• Effect of mutations in the beta5-beta7 loop on the structure and properties of human small heat shock protein HSP22 (PMID:17922839)
• These results suggested that the HspB8-Bag3 complex might stimulate the degradation of Htt43Q by macroautophagy. (PMID:18006506)
• HSPB8 is a candidate CDK-independent cyclin D1 target that can mediate its effects (PMID:18006821)
• HspB8 and Bag3: a new chaperone complex targeting misfolded proteins to macroautophagy. (PMID:18094623)
• Hsp22 induction represents a new aspect of the estrogenic response with potential significance for the biology of estrogen receptor-positive breast cancer cells. (PMID:18229450)
• Mutations in serine residues of HSP22 which are phosphorylated by cAMP-dependent protein kinase were accompanied by decrease of chaperone-like activity. (PMID:18298377)
• Activation of the bone morphogenetic protein receptors Alk3 and Bmpr2 by H11kinase/Hsp22 promotes cardiac cell growth and survival. (PMID:19246680)
• The results confirm predictions that Hsp22 belongs to the family of intrinsically disordered proteins with certain parts of its molecule retaining folded structure and undergoing reversible thermal unfolding. (PMID:19783089)
• Data show that the interaction between HspB6 and Bag3 requires the same regions that are involved in the HspB8-Bag3 association. (PMID:19845507)
• Data show that the two motor neuropathy-associated mutant HspB8 forms have abnormally increased binding to Ddx20. (PMID:20157854)
• HspB8 increases misfolded SOD1 clearance via autophagy. (PMID:20570967)
• Drosophila HSP67Bc is the functional ortholog of human HSPB8 and Dm-HSP67Bc induces autophagy via the eIF2alpha pathway. (PMID:20858900)
• phosphorylation of HspB8 by ERK1 might be important for regulation of interaction of HspB8 with different target proteins (PMID:21526341)
• These results demonstrated for the first time that Hsp22 regulates Sam68 expression and the ratio of Sam68 to Hsp22 may determine the proliferative potential of glioblastoma cells. (PMID:21678403)
• we observed upregulation of HSPB8 and BAG3 selectively in astrocytes located within the degenerated areas of patients with protein aggregation diseases (PMID:21696420)
• Overexpression of HSPB1, as well as HSPB6, HSPB7 and HSPB8 independently protect against tachycardia remodeling by attenuation of the RhoA GTPase pathway at different levels. (PMID:21731611)
• The complexes formed by Bag3 and HspB8 might have variable stoichiometry and can participate in different processes including clearing of the cell from improperly folded proteins. (PMID:21767525)
• present study demonstrates that HSPB8 is silenced by DNA methylation in hematopoietic malignant and normal cells (PMID:21914495)
• HSPB8 may play an important role in the protection of cells under lethal heat shock treatment, and the K141N mutation can impair the protective effect. (PMID:21983727)
• The results of this syudy suggested that defects in HspB8-mediated autophagy are likely to contribute to dHMNII pathology and their detection in peripheral blood mononuclear cells could be a useful, accessible biomarker for the disease. (PMID:21985219)
• We studied the HSPB1 and HSPB8 mutation occurrence in patients with distal hereditary motor neuropathy and those with the axonal form of Charcot-Marie-Tooth disease type 2 (PMID:22176143)
• findings show that during heat shock recovery NF-kappaB activates selective removal of misfolded or aggregated proteins by controlling expression of BAG3 and HSPB8 and by modulating the level of the BAG3-HspB8 complex (PMID:22302993)
• Mutant HSPB8 causes protein aggregates and a reduced mitochondrial membrane potential in dermal fibroblasts from distal hereditary motor neuropathy patients. (PMID:22595202)
• The expression of HspB8 inhibits the growth of genetically diverse melanoma cells that include caspase-1 activation outside of the realm of the inflammasome, mTORC1-dependent Beclin-1 upregulation and its cleavage by the activated caspase-1. (PMID:22898869)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	hspb8	ENSDARG00000058365
mus_musculus	Hspb8	ENSMUSG00000041548
rattus_norvegicus	Hspb8	ENSRNOG00000022392
drosophila_melanogaster	Hsp22	FBGN0001223
drosophila_melanogaster	Hsp23	FBGN0001224
drosophila_melanogaster	Hsp26	FBGN0001225
drosophila_melanogaster	Hsp67Ba	FBGN0001227
drosophila_melanogaster	Hsp67Bc	FBGN0001229
drosophila_melanogaster	l(2)efl	FBGN0011296
drosophila_melanogaster	CG14207	FBGN0031037
caenorhabditis_elegans		WBGENE00002011
caenorhabditis_elegans		WBGENE00002015
caenorhabditis_elegans		WBGENE00002016
caenorhabditis_elegans		WBGENE00002017
caenorhabditis_elegans		WBGENE00002018
caenorhabditis_elegans		WBGENE00002019
caenorhabditis_elegans		WBGENE00002020
caenorhabditis_elegans		WBGENE00002023
caenorhabditis_elegans		WBGENE00008591
caenorhabditis_elegans		WBGENE00008592
caenorhabditis_elegans	hsp-12.1	WBGENE00011906

Paralogs (8): HSPB6 (ENSG00000004776), HSPB1 (ENSG00000106211), CRYAB (ENSG00000109846), CRYAA (ENSG00000160202), HSPB3 (ENSG00000169271), HSPB2 (ENSG00000170276), HSPB7 (ENSG00000173641), HSPB9 (ENSG00000260325)

Protein

Protein identifiers

Heat shock protein beta-8 — Q9UJY1 (reviewed: Q9UJY1)

Alternative names: Alpha-crystallin C chain, E2-induced gene 1 protein, Heat shock protein family B member 8, Protein kinase H11, Small stress protein-like protein HSP22

All UniProt accessions (8): Q9UJY1, A0A6Q8PF95, A0A6Q8PGM6, A0A6Q8PGX5, A0A6Q8PHB1, A0A6Q8PHK6, A0A6Q8PHR2, H0YG30

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle. Displays temperature-dependent chaperone activity.

Subunit / interactions. Monomer. Forms a ternary complex with BAG3 and HSPA1A. Component of the chaperone-assisted selective autophagy (CASA) complex consisting of BAG3, HSPA8/HSC70, HSPB8 and STUB1/CHIP. Interacts with HSPB1. Interacts with DNAJB6. Interacts with BAG3.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Predominantly expressed in skeletal muscle and heart.

Disease relevance. Neuronopathy, distal hereditary motor, autosomal dominant 2 (HMND2) [MIM:158590] A form of distal hereditary motor neuronopathy, a heterogeneous group of neuromuscular disorders caused by selective degeneration of motor neurons in the anterior horn of the spinal cord, without sensory deficit in the posterior horn. The overall clinical picture consists of a classical distal muscular atrophy syndrome in the legs without clinical sensory loss. The disease starts with weakness and wasting of distal muscles of the anterior tibial and peroneal compartments of the legs. Later on, weakness and atrophy may expand to the proximal muscles of the lower limbs and/or to the distal upper limbs. The disease is caused by variants affecting the gene represented in this entry. Charcot-Marie-Tooth disease, axonal, type 2L (CMT2L) [MIM:608673] An autosomal dominant, axonal form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies (designated CMT1 when they are dominantly inherited) and primary peripheral axonal neuropathies (CMT2). Neuropathies of the CMT2 group are characterized by signs of axonal degeneration in the absence of obvious myelin alterations, normal or slightly reduced nerve conduction velocities, and progressive distal muscle weakness and atrophy. The disease is caused by variants affecting the gene represented in this entry. Myopathy, myofibrillar, 13, with rimmed vacuoles (MFM13) [MIM:621078] A form of myofibrillar myopathy, a group of chronic neuromuscular disorders characterized at ultrastructural level by disintegration of the sarcomeric Z disk and myofibrils, and replacement of the normal myofibrillar markings by small dense granules, or larger hyaline masses, or amorphous material. MFM13 is an autosomal dominant form characterized by progressive distal and proximal muscle weakness, muscle atrophy, and unsteady gait and walking difficulties. Symptoms usually begin in adulthood, although earlier disease onset has been reported in some cases. Muscle biopsy shows myofibrillar changes and rimmed vacuoles. Some patients have features of a peripheral motor or sensorimotor neuropathy. The disease is caused by variants affecting the gene represented in this entry.

Induction. By 17-beta-estradiol.

Similarity. Belongs to the small heat shock protein (HSP20) family.

RefSeq proteins (1): NP_055180* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001436	Alpha-crystallin/sHSP_animal	Family
IPR002068	A-crystallin/Hsp20_dom	Domain
IPR008978	HSP20-like_chaperone	Homologous_superfamily
IPR042790	HspB8_ACD	Domain
IPR043254	HSPB8	Family

Pfam: PF00011

UniProt features (18 total): sequence variant 8, modified residue 5, chain 1, domain 1, sequence conflict 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8S7A	X-RAY DIFFRACTION	1.95

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UJY1-F1	68.50	0.37

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (5): 24, 57, 63, 71, 78

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3371571	HSF1-dependent transactivation

MSigDB gene sets: 357 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, AP1_01, GOBP_REGULATION_OF_AUTOPHAGY, WALLACE_PROSTATE_CANCER_RACE_UP, FISCHER_G1_S_CELL_CYCLE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, KYNG_DNA_DAMAGE_DN, KYNG_DNA_DAMAGE_BY_4NQO, CHANDRAN_METASTASIS_DN, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_MACROAUTOPHAGY, YORDY_RECIPROCAL_REGULATION_BY_ETS1_AND_SP100_DN

GO Biological Process (2): cellular response to unfolded protein (GO:0034620), positive regulation of aggrephagy (GO:1905337)

GO Molecular Function (3): identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein folding chaperone complex (GO:0101031)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Cellular response to heat stress	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to unfolded protein	1
cellular response to topologically incorrect protein	1
positive regulation of macroautophagy	1
aggrephagy	1
regulation of aggrephagy	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular protein-containing complex	1

Protein interactions and networks

STRING

1588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPB8	BAG3	O95817	997
HSPB8	HSPA4	P34932	994
HSPB8	HSPA8	P11142	992
HSPB8	STUB1	Q9UNE7	986
HSPB8	HSPB2	Q16082	891
HSPB8	HSPB3	Q12988	864
HSPB8	DNAJB1	P25685	860
HSPB8	HSPB1	P04792	831
HSPB8	HSP90AB1	P08238	811
HSPB8	HSPH1	Q92598	790
HSPB8	HSP90AA1	P07900	763
HSPB8	MN1	Q10571	763
HSPB8	DNAJB6	O75190	750
HSPB8	DNAJB2	P25686	743
HSPB8	VPS29	Q9UBQ0	724

IntAct

103 interactions, top by confidence:

A	B	Type	Score
BAG3	HSPB8	psi-mi:“MI:0915”(physical association)	0.930
HSPB8	BAG3	psi-mi:“MI:0915”(physical association)	0.930
KCTD13	CUL3	psi-mi:“MI:0914”(association)	0.870
HSPB8	HSPB7	psi-mi:“MI:0915”(physical association)	0.850
HSPB7	HSPB8	psi-mi:“MI:0915”(physical association)	0.850
HSPB7	HSPB8	psi-mi:“MI:2364”(proximity)	0.850
QRICH1	HSPB8	psi-mi:“MI:0915”(physical association)	0.780
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
HSPB8	MLF2	psi-mi:“MI:0915”(physical association)	0.680
DLGAP4	LIN7A	psi-mi:“MI:0914”(association)	0.590
HSPB8	HSPB8	psi-mi:“MI:0915”(physical association)	0.580
HSPB8	DUSP12	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (225): HSPB8 (Two-hybrid), HSPB7 (Two-hybrid), QRICH1 (Two-hybrid), HSPB8 (Affinity Capture-MS), HSPB7 (Two-hybrid), HSPB8 (Two-hybrid), HSPB8 (Affinity Capture-Western), BAG3 (Two-hybrid), HSPB8 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS), HSPB8 (Affinity Capture-MS)

ESM2 similar proteins: A5JV83, O93591, P02487, P02497, P02500, P02506, P02507, P02508, P02509, P02510, P02511, P02512, P04792, P05811, P06904, P09887, P14602, P15990, P15991, P23927, P23928, P24622, P24623, P30218, P30219, P35385, P41316, P42929, P42930, P42931, Q00649, Q05557, Q05713, Q3T149, Q5EAC9, Q5ENY9, Q5R9K0, Q5RAB0, Q5S1U1, Q60HG8

Diamond homologs: A5JV83, O14558, P02487, P02488, P02489, P02507, P02510, P02511, P02512, P04120, P04792, P05811, P06581, P06582, P14602, P15991, P23927, P23928, P30218, P30219, P34696, P35385, P41316, P42929, P42930, P42931, P82147, P97541, Q00649, Q04757, Q05557, Q05713, Q148F8, Q1RI96, Q3T149, Q5EAC9, Q5ENY9, Q5R9K0, Q5RAB0, Q5S1U1

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
MAPK3	“up-regulates activity”	HSPB8	phosphorylation
PRKCA	“up-regulates activity”	HSPB8	phosphorylation
MAPK3	up-regulates	HSPB8	phosphorylation
PRKCA	up-regulates	HSPB8	phosphorylation
PKA	“down-regulates quantity by destabilization”	HSPB8	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
protein folding	5	12.0×	4e-03
negative regulation of apoptotic process	7	5.7×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

282 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	4
Uncertain significance	163
Likely benign	61
Benign	25

Top pathogenic / likely-pathogenic (14)

Variant ID	HGVS	Classification
1805628	NM_014365.3(HSPB8):c.508del (p.Gln170fs)	Pathogenic
2617	NM_014365.3(HSPB8):c.423G>C (p.Lys141Asn)	Pathogenic
2618	NM_014365.3(HSPB8):c.421A>G (p.Lys141Glu)	Pathogenic
2619	NM_014365.3(HSPB8):c.423G>T (p.Lys141Asn)	Pathogenic
3602737	NM_014365.3(HSPB8):c.525_529del (p.Thr176fs)	Pathogenic
3602739	NM_014365.3(HSPB8):c.576_579delinsCAG (p.Glu192fs)	Pathogenic
3767297	NM_014365.3(HSPB8):c.538_542del (p.Ser180fs)	Pathogenic
3767298	NM_014365.3(HSPB8):c.571del (p.Gln191fs)	Pathogenic
560412	NM_014365.3(HSPB8):c.422A>T (p.Lys141Met)	Pathogenic
972979	NM_014365.3(HSPB8):c.577_580dup (p.Thr194fs)	Pathogenic
560411	NM_014365.3(HSPB8):c.413A>C (p.Asn138Thr)	Likely pathogenic
584450	NM_014365.3(HSPB8):c.520_533del (p.Tyr174fs)	Likely pathogenic
915312	NM_014365.3(HSPB8):c.419C>T (p.Thr140Ile)	Likely pathogenic
986227	NM_014365.3(HSPB8):c.515dup (p.Pro173fs)	Likely pathogenic

SpliceAI

318 predictions. Top by Δscore:

Variant	Effect	Δscore
12:119187019:TTCCA:T	acceptor_loss	1.0000
12:119187020:TCCAG:T	acceptor_loss	1.0000
12:119187021:CCA:C	acceptor_loss	1.0000
12:119187022:CA:C	acceptor_loss	1.0000
12:119187023:A:AG	acceptor_gain	1.0000
12:119187024:G:GA	acceptor_gain	1.0000
12:119187084:ATCCA:A	donor_gain	1.0000
12:119187085:TCCA:T	donor_gain	1.0000
12:119187087:CAGTA:C	donor_loss	1.0000
12:119187088:AGT:A	donor_loss	1.0000
12:119187089:G:GG	donor_gain	1.0000
12:119187089:GTAA:G	donor_loss	1.0000
12:119179675:GTCTG:G	donor_gain	0.9900
12:119179676:TCTGG:T	donor_loss	0.9900
12:119179678:TGG:T	donor_loss	0.9900
12:119179680:G:GG	donor_gain	0.9900
12:119179681:TAAG:T	donor_loss	0.9900
12:119187023:AG:A	acceptor_gain	0.9900
12:119187024:GG:G	acceptor_gain	0.9900
12:119187024:GGC:G	acceptor_gain	0.9900
12:119187024:GGCA:G	acceptor_gain	0.9900
12:119187024:GGCAA:G	acceptor_gain	0.9900
12:119187086:CCA:C	donor_gain	0.9900
12:119187087:CA:C	donor_gain	0.9900
12:119187090:T:A	donor_loss	0.9900
12:119187091:AA:A	donor_loss	0.9900
12:119187092:AGTA:A	donor_loss	0.9800
12:119193694:CCTA:C	acceptor_loss	0.9800
12:119193695:CTAG:C	acceptor_loss	0.9800
12:119193697:A:AC	acceptor_loss	0.9800

AlphaMissense

1278 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:119179625:T:C	F105L	1.000
12:119179626:T:C	F105S	1.000
12:119179627:C:A	F105L	1.000
12:119179627:C:G	F105L	1.000
12:119179641:T:C	L110S	1.000
12:119187025:G:A	G123D	1.000
12:119187072:T:C	F139L	1.000
12:119187073:T:C	F139S	1.000
12:119187073:T:G	F139C	1.000
12:119187074:C:A	F139L	1.000
12:119187074:C:G	F139L	1.000
12:119187080:G:C	K141N	1.000
12:119187080:G:T	K141N	1.000
12:119193758:T:A	L164Q	1.000
12:119193758:T:C	L164P	1.000
12:119193764:T:A	I166N	1.000
12:119179598:T:A	W96R	0.999
12:119179598:T:C	W96R	0.999
12:119179600:G:C	W96C	0.999
12:119179600:G:T	W96C	0.999
12:119179625:T:A	F105I	0.999
12:119179626:T:G	F105C	0.999
12:119179641:T:G	L110W	0.999
12:119179668:T:A	V119E	0.999
12:119179676:T:C	S122P	0.999
12:119179679:G:C	G123R	0.999
12:119187030:C:G	H125D	0.999
12:119187031:A:C	H125P	0.999
12:119187085:T:C	I143T	0.999
12:119193728:T:A	V154E	0.999

dbSNP variants (sampled 300 via entrez): RS1000028174 (12:119186593 C>T), RS1000308660 (12:119192799 A>G), RS1000354596 (12:119189149 C>T), RS1000430198 (12:119177633 A>T), RS1000728639 (12:119193790 T>C,G), RS1000856244 (12:119181739 G>A), RS1000959983 (12:119182458 G>A), RS1000968125 (12:119187746 C>G), RS1001050969 (12:119187901 C>T), RS1001192343 (12:119177906 G>A), RS1001218256 (12:119194363 C>G,T), RS1001327046 (12:119182254 C>T), RS1001474960 (12:119178147 G>T), RS1001705126 (12:119183636 G>A,C), RS1001731426 (12:119194036 G>A)

Disease associations

OMIM: gene MIM:608014 | disease phenotypes: MIM:608673, MIM:158590, MIM:609500, MIM:621078, MIM:118220, MIM:617601, MIM:160500

GenCC curated gene-disease

Disease	Classification	Inheritance
neuronopathy, distal hereditary motor, type 2A	Strong	Autosomal dominant
Charcot-Marie-Tooth disease axonal type 2L	Strong	Autosomal dominant
myopathy, myofibrillar, 13, with rimmed vacuoles	Strong	Autosomal dominant
distal hereditary motor neuropathy type 2	Supportive	Autosomal dominant
autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
neuronopathy, distal hereditary motor, autosomal dominant	Definitive	AD

Mondo (10): Charcot-Marie-Tooth disease axonal type 2L (MONDO:0012096), neuronopathy, distal hereditary motor, type 2A (MONDO:0008025), myopathy, autophagic vacuolar, infantile-onset (MONDO:0012286), myopathy, myofibrillar, 13, with rimmed vacuoles (MONDO:0976133), peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease (MONDO:0015626), intellectual disability, autosomal dominant 46 (MONDO:0030911), distal myopathy (MONDO:0018949), distal hereditary motor neuropathy type 2 (MONDO:0015352), (MONDO:0018773)

Orphanet (5): Autosomal dominant Charcot-Marie-Tooth disease type 2L (Orphanet:99945), Distal hereditary motor neuropathy type 2 (Orphanet:139525), HSPB8-related autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome (Orphanet:476093), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal myopathy (Orphanet:599)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000011	Neurogenic bladder
HP:0000365	Hearing impairment
HP:0000819	Diabetes mellitus
HP:0000822	Hypertension
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001626	Abnormality of the cardiovascular system
HP:0001638	Cardiomyopathy
HP:0001761	Pes cavus
HP:0001771	Achilles tendon contracture
HP:0002093	Respiratory insufficiency
HP:0002149	Hyperuricemia
HP:0002380	Fasciculations
HP:0002460	Distal muscle weakness
HP:0002505	Loss of ambulation
HP:0002515	Waddling gait
HP:0002522	Areflexia of lower limbs
HP:0002527	Falls
HP:0002600	Hyporeflexia of lower limbs
HP:0002601	Paresis of extensor muscles of the big toe
HP:0002650	Scoliosis
HP:0002792	Reduced vital capacity
HP:0002878	Respiratory failure
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002936	Distal sensory impairment
HP:0002938	Lumbar hyperlordosis
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002279_95	PR interval in Tripanosoma cruzi seropositivity	4.000000e-08
GCST009391_288	Metabolite levels	9.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004462	PR interval
EFO:0010424	triacylglycerol 54:6 measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C580044	Distal Hereditary Motor Neuropathy, Type II (supp.)
C563561	Neuropathy, Distal Hereditary Motor, Type IIA (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

93 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Estradiol	affects reaction, decreases reaction, increases expression, decreases expression, affects binding (+3 more)	10
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, affects binding, increases reaction, increases expression	6
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
bisphenol A	decreases expression, increases expression	4
Benzo(a)pyrene	increases expression	3
Copper	decreases expression, increases expression, affects binding	3
Cyclosporine	affects cotreatment, increases expression	3
Aflatoxin B1	affects expression, increases expression	3
sodium arsenite	decreases expression, increases expression	2
entinostat	increases expression, affects cotreatment	2
Calcitriol	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Silicon Dioxide	increases expression	2
Silver	increases expression	2
Asbestos, Crocidolite	increases expression	2
Cadmium Chloride	increases expression	2
Raloxifene Hydrochloride	decreases expression, decreases reaction, increases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
methylmercuric chloride	increases expression	1
propionaldehyde	increases expression	1
lead acetate	increases expression	1
sodium arsenate	decreases expression, increases abundance	1
2-methyl-4-isothiazolin-3-one	increases expression	1
afimoxifene	decreases reaction, increases expression, decreases response to substance	1
zinc chromate	increases abundance, increases expression	1
ferrous chloride	increases expression	1
nickel sulfate	increases expression	1
cupric oxide	increases expression	1
butylparaben	increases expression	1
mercuric bromide	increases expression, affects cotreatment	1

Cellosaurus cell lines

8 cell lines: 4 finite cell line, 3 transformed cell line, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1U1	Abcam HeLa HSPB8 KO	Cancer cell line	Female
CVCL_B5LG	GM28283	Finite cell line	Male
CVCL_LH24	GM26095	Transformed cell line	Male
CVCL_LH25	GM26096	Finite cell line	Male
CVCL_LH26	GM26097	Transformed cell line	Female
CVCL_LH27	GM26098	Finite cell line	Female
CVCL_LH28	GM26099	Transformed cell line	Male
CVCL_LH33	GM26579	Finite cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.