HSPB1

protein-coding

heat shock protein family B (small) member 1, the group of Small heat shock proteins

Gene summary

This gene encodes a member of the small heat shock protein (HSP20) family of proteins. In response to environmental stress, the encoded protein translocates from the cytoplasm to the nucleus and functions as a molecular chaperone that promotes the correct folding of other proteins. This protein plays an important role in the differentiation of a wide variety of cell types. Expression of this gene is correlated with poor clinical outcome in multiple human cancers, and the encoded protein may promote cancer cell proliferation and metastasis, while protecting cancer cells from apoptosis. Mutations in this gene have been identified in human patients with Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. [provided by RefSeq, Aug 2017]

MANE transcript

NM_001540.5

Inheritance

ClinVar variants

P:52U:206B:85

Top phenotype

Neuronopathy, distal hereditary motor, autosomal dominant 3; Charcot-Marie-Tooth disease, axonal, type 2F

gnomAD constraint

pLI —, LoF o/e 1.26

Max pathogenic AF

—

Genomic locus

chr7:76,302,673-76,305,813

External References & Databases

Ensembl (ENSG00000106211)

Transcript & Mutation Effects

hg38 • Region Span ~3.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Charcot-Marie-Tooth disease axonal type 2FSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011687

Submitter: PanelApp Australia

Charcot-Marie-Tooth disease axonal type 2FDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011687

Submitter: ClinGen

HSPB1 was first reported in relation to Autosomal Dominant CMT2 and dHMN in 2004 (Evgrafov et al., PMID: 15122254). The disease is characterized by a predominantly motor neuropathy, with distal atrophy and weakness, and only late, subclinical sensory signs. The inheritance pattern of the two diseases is reported to be autosomal dominant. It has been proposed that mutations located in the C-terminal tail of the protein cause dHMN, however, is not supported by genotype-phenotype associations and the same variants can be associated with either phenotype in different families and within the same family. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism(s) AND inheritance pattern AND phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, dHMN type 2B (OMIM:608634). Recessive inheritance has been also described and will be reviewed separately. Sixteen variants (13 missense, 3 nonsense) that have been reported in 33 probands in 10 publications (PMIDs: 15122254, 18832141, 18952241, 18344398, 16155736, 16087758, 20870250, 19435728, 22734906, 29381233) More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached genetic evidence. A gain of function mechanism of pathogenicity is hypnotized for most of HSPB1 disease-associated variants on the basis of the tendency of mutant proteins to aggregate, sequestering the WT protein, the aberrant dimerization and interaction with substrate proteins, like Neurofilaments, by mutant HSPB1 proteins and the absence of a peripheral nervous system phenotype in KO mice. This gene-disease association is also supported by several transgenic models. In one of them (PMIDs: 21785432), HSPB1 S135F mutation (the most common CMT-associated HSPB1 variant) expressed selectively in neurons induce progressive motor impairment, signs of sensory defects and electrophysiological signs of axonal neuropathy. DRG neurons expressing this variant show impaired mitochondrial transport and reduced acetylated tubulin. The treatment with HDAC6, a tubulin de-acetylator, rescues the motor phenotype. Also transgenic mice expressing HSPB1 P182L mutation in neurons showed motor impairment, axonal loss and denervation. In summary, HSPB1 is definitively associated with autosomal dominant CMT2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Charcot-Marie-Tooth disease axonal type 2FSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011687

Submitter: Labcorp Genetics (formerly Invitae)

neuronopathy, distal hereditary motor, type 2BMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0012080

Submitter: Ambry Genetics

Charcot-Marie-Tooth disease axonal type 2FDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011687

Submitter: Illumina

distal hereditary motor neuropathy type 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015352

Submitter: Orphanet

Charcot-Marie-Tooth disease axonal type 2FSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011687

Submitter: Orphanet

Clinical Genomic Database (CGD)

Neuronopathy, distal hereditary motor, autosomal dominant 3; Charcot-Marie-Tooth disease, axonal, type 2FAD

Manifestation: 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

Refs: 11528513; 15122254; 16087758; 18325928; 18832141; 18952241; 20301462; 20870250; 22176143

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to HSPB1 variants in ClinVar

13 Conditions Cataloged

Charcot-Marie-Tooth disease axonal type 2FTotal: 311

not providedTotal: 122

Inborn genetic diseasesTotal: 74

Neuronopathy, distal hereditary motor, type 2BTotal: 43

Charcot-Marie-Tooth diseaseTotal: 42

HSPB1-related disorderTotal: 41

not specifiedTotal: 37

Charcot-Marie-Tooth disease type 4Total: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001540.5. 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			3 clinvar	75 clinvar	1 clinvar	79
missense	8 clinvar	21 clinvar	183 clinvar	9 clinvar		221
nonsense	2 clinvar	3 clinvar	7 clinvar			12
start loss		1 clinvar	2 clinvar			3
frameshift	3 clinvar	14 clinvar	9 clinvar			26
splice donor/acceptor (+/-2bp)			2 clinvar			2
Total	13	39	206	84	1	343

Highest pathogenic variant AF is 0.00004588305

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001540.5	RefSeq	NP_001531.1	3	MANE Select
ENST00000248553.7	Ensembl	ENSP00000248553.6	3	MANE Select
ENST00000429938.1	Ensembl	ENSP00000405285.1	1	Standard
ENST00000429938.2	Ensembl	ENSP00000405285.1	1	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
hspb1	Danio rerio	Structure: peripheral neuron Quality: branchiness abnormal

Gene / Model

Organism

Observed Phenotype

hspb1

Danio rerio

Structure: peripheral neuron

Quality: branchiness

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

VEGF signaling pathway - Homo sapiens (human)
Amoebiasis - Homo sapiens (human)
MAPK signaling pathway - Homo sapiens (human)
Epstein-Barr virus infection - Homo sapiens (human)
Apoptosis-related network due to altered Notch3 in ovarian cancer

Biological Process

retina homeostasis
regulation of protein phosphorylation
regulation of translational initiation
negative regulation of protein kinase activity
response to unfolded protein

Molecular Function

RNA binding
protein kinase C binding
protein binding
protein kinase C inhibitor activity
protein kinase binding

Cellular Component

proteasome complex
extracellular space
nucleus
cytoplasm
spindle

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000248553
Coding exons: 3
Length: 1752
Individuals with no LoFs: 125520
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125547
p: 0.000108

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.515	136	120	1.13	0.00000590	1275
Missense (PolyPhen)		39	37.73	1.0337		420
Synonymous	-2.68	79	54.0	1.46	0.00000277	427
Loss of Function	-0.633	9	7.17	1.26	3.18e-7	71

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00014	0.00013	rare
South Asian	0.000065	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding- competent state (PubMed:10383393, PubMed:20178975). Plays a role in stress resistance and actin organization (PubMed:19166925). Through its molecular chaperone activity may regulate numerous biological processes including the phosphorylation and the axonal transport of neurofilament proteins (PubMed:23728742). {ECO:0000269|PubMed:10383393, ECO:0000269|PubMed:19166925, ECO:0000269|PubMed:20178975, ECO:0000269|PubMed:23728742}.;
Disease: DISEASE: Charcot-Marie-Tooth disease 2F (CMT2F) [MIM:606595]: A 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. Onset of Charcot-Marie-Tooth disease type 2F is between 15 and 25 years with muscle weakness and atrophy usually beginning in feet and legs (peroneal distribution). Upper limb involvement occurs later. {ECO:0000269|PubMed:15122254, ECO:0000269|PubMed:20178975, ECO:0000269|PubMed:22176143, ECO:0000269|PubMed:22206013, ECO:0000269|PubMed:23728742}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Neuronopathy, distal hereditary motor, 2B (HMN2B) [MIM:608634]: 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:15122254, ECO:0000269|PubMed:18832141, ECO:0000269|PubMed:18952241, ECO:0000269|PubMed:20178975, ECO:0000269|PubMed:20870250, ECO:0000269|PubMed:22176143, ECO:0000269|PubMed:23643870, ECO:0000269|PubMed:23728742, ECO:0000269|PubMed:23948568, ECO:0000269|PubMed:25965061, ECO:0000269|PubMed:28144995}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.796

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.992

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium