HSPB8
protein-codingheat shock protein family B (small) member 8, the group of Small heat shock proteins
Gene summary
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. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~53.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0018773
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012096
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0012096
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015362
Submitter: ClinGen
HSPB8 mutations are predominantly associated with distal hereditary motor neuropathy (dHMN) type 2; however, it can also cause Charcot-Marie-Tooth type 2 (CMT2) (Nakhro et at. 2013. PMID: 23796487), although sensory involvement is less common. HSPB8 encodes for the heat-shock 22-kDa protein 8, which is a member of the small heat shock protein family. Its main function is the delivery of misfolded proteins to the protein degradation pathway. It participates in the chaperone-selective induced autophagy (CASA) together with BAG3, another known CMT gene. HSPB8 mutations are predominantly located at the conserved alpha-crystallin domain, which is essential for the structure and function of the protein. A mutational hot-spot has been identified at the K141 residue. Four different mutations have been reported at this residue. The K141 residue lies on a constraint coding region of the gene based on gnomAD, which is above the 90th percentile for constraint, which supports pathogenicity for the mutations. HSPB8 was first identified as a disease gene by linkage analysis in two large autosomal dominant families with dHMN type 2 (Irobi et at. 2004. PMID: 1512225). Families shared the same variant, K141N. The same locus was also identified in a large Chinese family; however, CMT was the described phenotype and not dHMN as previously reported (Tang et at. 2005. PMID: 15565283). HSPB8 has also been reported in families with distal myopathy with motor neuropathy (Ghaoui et at. 2016. PMID: 26718575). HSPB8 is highly expressed in the peripheral nerve and it interacts with two known CMT genes, BAG3 and HSPB1. Expression of the HSPB8 mutants, K141N and K141E resulted in the accumulation of toxic aggregates in cells and reduced cell viability (Irobi et at. 2004. PMID: 15122253). Mutations also resulted in reduced chaperone activity of the protein (Carra et al., 2005; PMID: 15879436). Expression of mutants in rat motor neurons resulted in abnormal formation of beaded-like structures and reduced neurite length and number (Irobi et al., 2010; PMID: 20538880). A knock-in mouse model carrying the K141E mutation developed progressive motor deficits, including declined locomotor performance, decreased CMAP amplitude and decreased muscle strength. Sciatic nerve from mice showed several axonal degeneration and HSPB8 protein aggregation. In summary, HSPB8 genetic and functional evidence was classified as DEFINITIVE.
Inheritance Pattern: AD
Disease ID:MONDO:0008025
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0008025
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015352
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0976133
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0012096
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Musculoskeletal; Neurologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to HSPB8 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014365.3. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 44 | 4 | 49 | ||
| missense | 4 | 3 | 130 | 11 | 1 | 149 |
| nonsense | 4 | 4 | ||||
| start loss | 0 | |||||
| frameshift | 6 | 4 | 10 | 20 | ||
| splice donor/acceptor (+/-2bp) | 0 | |||||
| Total | 10 | 7 | 145 | 55 | 5 | 222 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055180.1 | 3 | MANE Select | |
| Ensembl | ENSP00000281938.3 | 3 | MANE Select | |
| Ensembl | ENSP00000441541.1 | 4 | Standard | |
| Ensembl | ENSP00000502352.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Biological Process
- protein phosphorylation
- cellular response to unfolded protein
- regulation of cellular response to heat
- positive regulation of aggrephagy
Molecular Function
- protein kinase activity
- protein binding
- identical protein binding
- protein homodimerization activity
Cellular Component
- nucleus
- nucleoplasm
- cytoplasm
- cytosol
- chaperone complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000281938
- Coding exons
- 3
- Length
- 42490
- Individuals with no LoFs
- 125743
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 5
- Defined
- 125748
- p
- 0.0000199
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0269 | 110 | 111 | 0.993 | 0.00000612 | 1270 |
| Missense (PolyPhen) | 32 | 37.2 | 0.86021 | 464 | ||
| Synonymous | -0.464 | 47 | 43.1 | 1.09 | 0.00000239 | 404 |
| Loss of Function | 1.35 | 3 | 6.78 | 0.442 | 3.45e-7 | 70 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000035 | 0.000035 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Displays temperature-dependent chaperone activity.;
- Disease
- DISEASE: Neuronopathy, distal hereditary motor, 2A (HMN2A) [MIM:158590]: A neuromuscular disorder. Distal hereditary motor neuronopathies constitute 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. {ECO:0000269|PubMed:15122253, ECO:0000269|PubMed:28144995}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Charcot-Marie-Tooth disease 2L (CMT2L) [MIM:608673]: An 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. {ECO:0000269|PubMed:15565283}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.221
Intolerance Scores
- LoFtool
- 0.229
- RVIS EVS
- 0.22
- RVIS percentile EVS
- 67.92
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.980
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |