HSPB3

Summary

HSPB3 (heat shock protein family B (small) member 3, HGNC:5248) is a protein-coding gene on chromosome 5q11.2, encoding Heat shock protein beta-3 (Q12988). Inhibitor of actin polymerization.

This gene encodes a muscle-specific small heat shock protein. A mutation in this gene is the cause of autosomal dominant distal hereditary motor neuropathy type 2C.

Source: NCBI Gene 8988 — RefSeq curated summary.

At a glance

• Gene–disease (curated): distal hereditary motor neuropathy type 2 (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 82 total
• Phenotypes (HPO): 16
• MANE Select transcript: NM_006308

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5248
Approved symbol	HSPB3
Name	heat shock protein family B (small) member 3
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Aliases	HSPL27
Ensembl gene	ENSG00000169271
Ensembl biotype	protein_coding
OMIM	604624
Entrez	8988

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000302005

RefSeq mRNA: 1 — MANE Select: NM_006308 NM_006308

CCDS: CCDS3961

Canonical transcript exons

ENST00000302005 — 1 exons

Exon	Start	End
ENSE00001128066	54455699	54456377

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 99.56.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1442 / max 303.3401, expressed in 367 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56438	2.9834	358
56437	0.1119	52
203557	0.0490	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.56	gold quality
left ventricle myocardium	UBERON:0006566	99.47	gold quality
myocardium	UBERON:0002349	99.35	gold quality
apex of heart	UBERON:0002098	99.33	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.12	gold quality
right atrium auricular region	UBERON:0006631	99.10	gold quality
cardiac atrium	UBERON:0002081	99.09	gold quality
heart left ventricle	UBERON:0002084	98.85	gold quality
cardiac ventricle	UBERON:0002082	98.84	gold quality
triceps brachii	UBERON:0001509	98.71	gold quality
biceps brachii	UBERON:0001507	98.41	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.22	gold quality
diaphragm	UBERON:0001103	97.99	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.90	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.86	gold quality
gastrocnemius	UBERON:0001388	97.46	gold quality
quadriceps femoris	UBERON:0001377	97.37	gold quality
vastus lateralis	UBERON:0001379	97.36	gold quality
gluteal muscle	UBERON:0002000	97.27	gold quality
skeletal muscle tissue	UBERON:0001134	96.94	gold quality
tibialis anterior	UBERON:0001385	96.51	gold quality
vena cava	UBERON:0004087	96.36	gold quality
heart	UBERON:0000948	96.29	gold quality
muscle organ	UBERON:0001630	96.02	gold quality
deltoid	UBERON:0001476	95.90	gold quality
muscle of leg	UBERON:0001383	95.52	gold quality
body of tongue	UBERON:0011876	95.17	gold quality
muscle tissue	UBERON:0002385	95.16	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.77	gold quality
mucosa of stomach	UBERON:0001199	85.13	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.64

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HNF4A

miRNA regulators (miRDB)

8 targeting HSPB3, 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-548C-3P	99.99	74.01	7587
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-141-5P	99.57	67.86	897
HSA-MIR-892A	99.54	68.16	1141
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-299-3P	97.73	66.67	773
HSA-MIR-624-5P	96.00	68.88	728

Literature-anchored findings (GeneRIF, showing 10)

• 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)
• an HSPB3 mutation associated with an axonal motor neuropathy (PMID:20142617)
• HspB3 exhibits chaperone-like activity. (PMID:22610661)
• This study showed that the endogenous HSPB3 protein distribution in the spinal cords of chicken and mouse embryos and in the postnatal nervous system of human. (PMID:27567740)
• HSPB2 competes with HSPB8 for binding to BAG3. In contrast, HSPB3 negatively regulates HSPB2 association with BAG3. (PMID:28181153)
• We identified a novel HSPB3 mutation (p.Tyr118His) in a Korean Charcot-Marie-Tooth disease type 2 family (PMID:29341343)
• High HSPB3 expression is associated with poor relapse-free survival (RFS) and overall survival (OS) of patients with colorectal adenocarcinoma. (PMID:31709619)
• Small heat-shock protein HSPB3 promotes myogenesis by regulating the lamin B receptor. (PMID:33958580)
• Evaluation of the Small Heat Shock Protein Family Members HSPB2 and HSPB3 in Bladder Cancer Prognosis and Progression. (PMID:36768927)
• PINK1 and Parkin rescue motor defects and mitochondria dysfunction induced by a patient-derived HSPB3 mutant in Drosophila models. (PMID:37804589)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	hspb3	ENSDARG00000067714
mus_musculus	Hspb3	ENSMUSG00000051456
rattus_norvegicus	Hspb3	ENSRNOG00000010992
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), HSPB8 (ENSG00000152137), CRYAA (ENSG00000160202), HSPB2 (ENSG00000170276), HSPB7 (ENSG00000173641), HSPB9 (ENSG00000260325)

Protein

Protein identifiers

Heat shock protein beta-3 — Q12988 (reviewed: Q12988)

Alternative names: Heat shock 17 kDa protein, Heat shock protein family B member 3, Protein 3

All UniProt accessions (2): Q12988, Q6ICS9

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of actin polymerization.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Neuronopathy, distal hereditary motor, autosomal dominant 4 (HMND4) [MIM:613376] 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.

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

RefSeq proteins (1): NP_006299* (*=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
IPR033894	HSPB3	Domain

Pfam: PF00011

UniProt features (4 total): sequence variant 2, chain 1, domain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6F2R	X-RAY DIFFRACTION	3.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q12988-F1	70.30	0.29

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 107 (showing top): NKX25_02, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, CAGCTG_AP4_Q5, MODULE_59, BROWNE_HCMV_INFECTION_14HR_DN, TGANTCA_AP1_C, WANG_CISPLATIN_RESPONSE_AND_XPC_DN, MEF2_Q6_01, CTAWWWATA_RSRFC4_Q2, GOBP_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOCC_NUCLEAR_SPECK, GOCC_NUCLEAR_BODY, chr5q11, GOCC_RIBONUCLEOPROTEIN_GRANULE, MEF2_03

GO Biological Process (1): response to unfolded protein (GO:0006986)

GO Molecular Function (0):

GO Cellular Component (3): nucleus (GO:0005634), cytoplasm (GO:0005737), nuclear speck (GO:0016607)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
response to topologically incorrect protein	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

2672 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HSPB3	IGF1	P01343	991
HSPB3	INS	P01308	990
HSPB3	CYCS	P00001	989
HSPB3	HSPA4	P34932	988
HSPB3	BCL2	P10415	988
HSPB3	IGF2	P01344	984
HSPB3	PLEC	Q15149	948
HSPB3	AKT1	P31749	923
HSPB3	HSP90AB1	P08238	916
HSPB3	HSP90AA1	P07900	908
HSPB3	EIF4G1	Q04637	907
HSPB3	HSPA8	P11142	900
HSPB3	HSPA1A	P08107	886
HSPB3	HSPB8	Q9UJY1	864
HSPB3	HSPBAP1	Q96EW2	856

IntAct

20 interactions, top by confidence:

A	B	Type	Score
HSPB3	H3-4	psi-mi:“MI:0915”(physical association)	0.400
HSPB3	HSPB8	psi-mi:“MI:0915”(physical association)	0.370
TCAP	HSPB3	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	UNC119	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	LSM14B	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	BBOX1	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	PRP4K	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	RIF1	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	SETDB1	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	ZZEF1	psi-mi:“MI:0915”(physical association)	0.000
ANP32A	HSPB3	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	MED31	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	DKFZP564B147	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	RBM48	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	OLFML3	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	MED8	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	MRPL38	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	NEFL	psi-mi:“MI:0915”(physical association)	0.000
HSPB3	RAMP3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): ANP32A (Two-hybrid), MED31 (Two-hybrid), FAM127B (Two-hybrid), RBM48 (Two-hybrid), OLFML3 (Two-hybrid), MED8 (Two-hybrid), MRPL38 (Two-hybrid), NSMF (Two-hybrid), RAMP3 (Two-hybrid), BBOX1 (Two-hybrid), PRPF4B (Two-hybrid), LRIF1 (Two-hybrid), SETDB1 (Two-hybrid), ZZEF1 (Two-hybrid), UNC119 (Two-hybrid)

ESM2 similar proteins: A0A3Q7ELQ2, F4I1X0, F4IEY4, O23090, O23487, O49710, O64564, O81822, O81900, P05477, P0CH01, P0DKI5, P19242, P19244, P29830, P46516, Q06003, Q12988, Q2HIV9, Q2KHU9, Q39818, Q3EBR4, Q6AY01, Q6NLV0, Q7X843, Q7Y0W3, Q7Y0W5, Q7YZT0, Q84K79, Q8GZ84, Q8LST2, Q8S8S7, Q8W2F1, Q943E9, Q94A51, Q94HV8, Q9FGD7, Q9FHQ3, Q9FIT9, Q9FJ16

Diamond homologs: O12984, O12988, O13224, O14558, O35878, O73919, O93591, P02470, P02472, P02474, P02475, P02476, P02477, P02478, P02479, P02480, P02482, P02483, P02484, P02485, P02486, P02487, P02488, P02489, P02492, P02493, P02494, P02497, P02498, P02499, P02500, P02501, P02502, P02503, P02504, P02505, P02506, P02507, P02508, P02509

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	53
Likely benign	14
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

202 predictions. Top by Δscore:

Variant	Effect	Δscore
5:54456153:GATG:G	donor_gain	0.7700
5:54456102:GA:G	donor_gain	0.7600
5:54456103:A:G	donor_gain	0.7200
5:54456140:G:GG	donor_gain	0.7200
5:54456139:A:AG	donor_gain	0.7000
5:54456275:G:T	donor_gain	0.6800
5:54456015:G:GT	donor_gain	0.6600
5:54456275:G:GT	donor_gain	0.6600
5:54456222:G:GT	donor_gain	0.6400
5:54456124:G:GT	donor_gain	0.6300
5:54455861:TCTAG:T	donor_gain	0.6000
5:54456233:GAC:G	donor_gain	0.6000
5:54455990:C:T	donor_gain	0.5900
5:54456101:GGA:G	donor_gain	0.5900
5:54456115:T:TG	donor_gain	0.5900
5:54456172:A:G	donor_gain	0.5900
5:54456209:G:GA	donor_gain	0.5900
5:54456211:TGG:T	donor_gain	0.5800
5:54456215:A:G	donor_gain	0.5800
5:54456171:GATTT:G	donor_gain	0.5700
5:54456212:GGA:G	donor_gain	0.5700
5:54456213:G:GT	donor_gain	0.5700
5:54456216:G:GG	donor_gain	0.5700
5:54456242:ACATC:A	donor_gain	0.5600
5:54456091:G:GT	donor_gain	0.5400
5:54456103:A:AG	donor_gain	0.5400
5:54456152:AGAT:A	donor_gain	0.5300
5:54456306:GAAT:G	donor_gain	0.5300
5:54456199:G:GT	donor_gain	0.5200
5:54456241:GACAT:G	donor_gain	0.5200

AlphaMissense

970 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:54456027:T:C	F80L	0.996
5:54456029:C:A	F80L	0.996
5:54456029:C:G	F80L	0.996
5:54456136:G:C	R116P	0.991
5:54456028:T:C	F80S	0.988
5:54456205:T:C	L139S	0.987
5:54456076:T:A	I96K	0.986
5:54456129:T:C	F114L	0.986
5:54456131:C:A	F114L	0.986
5:54456131:C:G	F114L	0.986
5:54456130:T:C	F114S	0.981
5:54456070:T:C	L94P	0.979
5:54456082:C:A	A98E	0.978
5:54456199:G:T	G137V	0.978
5:54456076:T:G	I96R	0.977
5:54456114:T:C	F109L	0.975
5:54456116:T:A	F109L	0.975
5:54456116:T:G	F109L	0.975
5:54456049:T:A	I87N	0.974
5:54456052:A:C	Q88P	0.973
5:54456073:T:C	L95P	0.971
5:54456076:T:C	I96T	0.971
5:54456125:A:C	R112S	0.971
5:54456125:A:T	R112S	0.971
5:54456124:G:T	R112I	0.970
5:54456124:G:C	R112T	0.969
5:54456040:A:T	D84V	0.968
5:54456199:G:A	G137E	0.968
5:54456057:T:C	F90L	0.967
5:54456059:C:A	F90L	0.967

dbSNP variants (sampled 300 via entrez): RS1001091437 (5:54456830 TA>T), RS1001915163 (5:54456744 A>G,T), RS1002857904 (5:54453866 G>A), RS1003189712 (5:54455047 G>C), RS1003631791 (5:54455278 A>G), RS1005100554 (5:54453834 G>A), RS1007695767 (5:54455350 C>T), RS1007728733 (5:54455565 A>G), RS1010864976 (5:54456303 C>A,T), RS1012415469 (5:54453823 C>T), RS1013416507 (5:54454940 T>C), RS1013426500 (5:54456409 T>C), RS1013709502 (5:54456818 A>G), RS1014049263 (5:54454637 C>G), RS1015358047 (5:54454489 T>C)

Disease associations

OMIM: gene MIM:604624 | disease phenotypes: MIM:613376

GenCC curated gene-disease

Disease	Classification	Inheritance
distal hereditary motor neuropathy type 2	Supportive	Autosomal dominant
neuronopathy, distal hereditary motor, type 2C	Limited	Autosomal dominant

Mondo (3): neuronopathy, distal hereditary motor, type 2C (MONDO:0013243), Charcot-Marie-Tooth disease type 2 (MONDO:0018993), distal hereditary motor neuropathy type 2 (MONDO:0015352)

Orphanet (2): Distal hereditary motor neuropathy type 2 (Orphanet:139525), Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001288	Gait disturbance
HP:0003376	Steppage gait
HP:0003388	Easy fatigability
HP:0003438	Absent Achilles reflex
HP:0003445	EMG: neuropathic changes
HP:0003677	Slowly progressive
HP:0006844	Absent patellar reflexes
HP:0007149	Distal upper limb amyotrophy
HP:0008944	Distal lower limb amyotrophy
HP:0008954	Intrinsic hand muscle atrophy
HP:0008959	Distal upper limb muscle weakness
HP:0009053	Distal lower limb muscle weakness
HP:0009830	Peripheral neuropathy
HP:0011462	Young adult onset
HP:0030237	Hand muscle weakness

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005204_1	Systolic blood pressure (dietary potassium intake interaction)	1.000000e-09
GCST009439_17	Age-related cognitive decline (language) (slope of z-scores)	1.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0006335	systolic blood pressure
EFO:0008470	dietary potassium intake measurement
EFO:0007710	cognitive decline measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580044	Distal Hereditary Motor Neuropathy, Type II (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
sulforaphane	decreases expression	1
incobotulinumtoxinA	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Amphotericin B	increases expression	1
Benzo(a)pyrene	increases methylation, affects methylation	1
Calcitriol	decreases expression	1
Doxorubicin	decreases expression	1
Triclosan	decreases expression	1
Paclitaxel	increases expression	1
Cadmium Chloride	decreases reaction, increases metabolic processing	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease