DNAJB2

Summary

DNAJB2 (DnaJ heat shock protein family (Hsp40) member B2, HGNC:5228) is a protein-coding gene on chromosome 2q35, encoding DnaJ homolog subfamily B member 2 (P25686). Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family.

This gene is almost exclusively expressed in the brain, mainly in the neuronal layers. It encodes a protein that shows sequence similarity to bacterial DnaJ protein and the yeast homologs. In bacteria, this protein is implicated in protein folding and protein complex dissociation. Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 3300 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease axonal type 2T (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 342 total — 10 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 12
• MANE Select transcript: NM_006736

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5228
Approved symbol	DNAJB2
Name	DnaJ heat shock protein family (Hsp40) member B2
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	HSPF3, CMT2T
Ensembl gene	ENSG00000135924
Ensembl biotype	protein_coding
OMIM	604139
Entrez	3300

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 retained_intron, 8 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000336576, ENST00000392086, ENST00000392087, ENST00000421532, ENST00000425450, ENST00000439026, ENST00000442681, ENST00000463463, ENST00000470530, ENST00000472019, ENST00000473750, ENST00000476254, ENST00000477917, ENST00000480537, ENST00000481815, ENST00000482988, ENST00000485220, ENST00000487855, ENST00000683651, ENST00000684599, ENST00000933785

RefSeq mRNA: 2 — MANE Select: NM_006736 NM_001039550, NM_006736

CCDS: CCDS2439, CCDS46519

Canonical transcript exons

ENST00000336576 — 9 exons

Exon	Start	End
ENSE00001422614	219284632	219286895
ENSE00001589801	219279366	219279518
ENSE00003463024	219279798	219279898
ENSE00003467684	219283133	219283235
ENSE00003632977	219280578	219280687
ENSE00003658169	219283419	219283489
ENSE00003660776	219281939	219282061
ENSE00003673301	219281718	219281771
ENSE00003787797	219282837	219282929

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 99.14.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 56.7074 / max 1040.5450, expressed in 1804 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25440	44.2886	1782
25441	8.2124	1713
25442	2.5451	1048
25439	0.8574	388
25443	0.4888	20
25444	0.1718	77
25438	0.1036	30
25445	0.0398	25

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	99.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.80	gold quality
cerebellar hemisphere	UBERON:0002245	98.66	gold quality
spinal cord	UBERON:0002240	98.62	gold quality
right frontal lobe	UBERON:0002810	98.62	gold quality
cerebellar cortex	UBERON:0002129	98.59	gold quality
adenohypophysis	UBERON:0002196	98.09	gold quality
amygdala	UBERON:0001876	98.07	gold quality
cingulate cortex	UBERON:0003027	97.97	gold quality
anterior cingulate cortex	UBERON:0009835	97.96	gold quality
prefrontal cortex	UBERON:0000451	97.95	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.95	gold quality
tibial nerve	UBERON:0001323	97.62	gold quality
pituitary gland	UBERON:0000007	97.61	gold quality
cerebellum	UBERON:0002037	97.60	gold quality
skin of leg	UBERON:0001511	97.52	gold quality
nucleus accumbens	UBERON:0001882	97.49	gold quality
right adrenal gland	UBERON:0001233	97.48	gold quality
left adrenal gland cortex	UBERON:0035825	97.47	gold quality
left adrenal gland	UBERON:0001234	97.42	gold quality
left testis	UBERON:0004533	97.41	gold quality
right adrenal gland cortex	UBERON:0035827	97.41	gold quality
apex of heart	UBERON:0002098	97.30	gold quality
corpus callosum	UBERON:0002336	97.28	gold quality
hypothalamus	UBERON:0001898	97.25	gold quality
skin of abdomen	UBERON:0001416	97.23	gold quality
putamen	UBERON:0001874	97.16	gold quality
right testis	UBERON:0004534	97.14	gold quality
gastrocnemius	UBERON:0001388	97.09	gold quality
right lobe of thyroid gland	UBERON:0001119	97.08	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

39 targeting DNAJB2, 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-4692	100.00	67.32	2066
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4310	99.59	68.84	2527
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-3978	99.24	68.39	2201
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-619-5P	98.57	64.97	1988
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-3670	97.88	64.39	763

Literature-anchored findings (GeneRIF, showing 13)

• data provide evidence that cytoplasmic chaperones HSJ1a and HSJ1b when targeted to the endoplasmic reticulum can influence the folding and processing of rhodopsin (PMID:12754272)
• HSJ1 is a neuronal shuttling factor for the sorting of chaperone clients to the proteasome. (PMID:15936278)
• Cystamine and cysteamine increase brain levels of BDNF in Huntington disease via HSJ1b and transglutaminase (PMID:16604191)
• Damaging exercise induced the expression of capZalpha, MCIP1, CARP1, DNAJB2, c-myc, and junD, each of which are likely involved in skeletal muscle growth, remodeling, and stress management. (PMID:18321953)
• Data show that DNAJB2 is expressed in skeletal muscle at the neuromuscular junction of normal fibers, in the cytoplasm and membrane of regenerating fibers, and in protein aggregates and vacuoles in protein aggregate myopathies. (PMID:20395441)
• a mutation causing a loss-of-function of HSJ1 is linked to a pure lower motor neuron disease, strongly suggesting that HSJ1 also plays an important and specific role in motor neurons. (PMID:22522442)
• HSJ1a acts on mutant SOD1 through a combination of chaperone, co-chaperone and pro-ubiquitylation activity. (PMID:24023695)
• The results of this study confirm that HSJ1 mutations are a rare but detectable cause of autosomal recessive dHMN and CMT2. (PMID:25274842)
• Study describes the identi fi cation of the fi rst deletion reported at the DNAJB2 locus, further expanding its phenotypic and genotypic spectrums as well as its disease-associated mechanisms with spinal muscular atrophy and parkinsonism. (PMID:27449489)
• Our results disclose a novel interplay between ubiquitin- and phosphorylation-dependent signalling, and represent the first report of a regulatory mechanism for UIM-dependent function. They also suggest that CK2 inhibitors could release the full neuroprotective potential of HSJ1, and deserve future interest as therapeutic strategies for neurodegenerative disease. (PMID:28031292)
• DNAJB2 expression in healthy human palatal mucosa is strongly negatively correlated with serum cotinine levels (PMID:31682009)
• DNAJB2-related Charcot-Marie-Tooth disease type 2: Pathomechanism insights and phenotypic spectrum widening. (PMID:35286755)
• The heat shock protein DNAJB2 as a novel biomarker for essential thrombocythemia diagnosis associated with immune infiltration. (PMID:36746103)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dnajb2	ENSMUSG00000026203
rattus_norvegicus	Dnajb2	ENSRNOG00000019506
drosophila_melanogaster	CG2887	FBGN0030207
drosophila_melanogaster	CG5001	FBGN0031322
drosophila_melanogaster	CG3061	FBGN0038195
drosophila_melanogaster	CG30156	FBGN0050156
drosophila_melanogaster	DnaJ-1	FBGN0263106
caenorhabditis_elegans		WBGENE00001019
caenorhabditis_elegans		WBGENE00001044

Paralogs (11): DNAJB11 (ENSG00000090520), DNAJB6 (ENSG00000105993), DNAJB9 (ENSG00000128590), DNAJB1 (ENSG00000132002), DNAJB5 (ENSG00000137094), DNAJB12 (ENSG00000148719), DNAJB4 (ENSG00000162616), DNAJB14 (ENSG00000164031), DNAJB7 (ENSG00000172404), DNAJB8 (ENSG00000179407), DNAJB13 (ENSG00000187726)

Protein

Protein identifiers

DnaJ homolog subfamily B member 2 — P25686 (reviewed: P25686)

Alternative names: Heat shock 40 kDa protein 3, Heat shock protein J1

All UniProt accessions (6): C9J1G2, C9JRD2, C9JX00, C9JXB9, E7ETU0, P25686

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a co-chaperone, regulating the substrate binding and activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family. In parallel, also contributes to the ubiquitin-dependent proteasomal degradation of misfolded proteins. Thereby, may regulate the aggregation and promote the functional recovery of misfolded proteins like HTT, MC4R, PRKN, RHO and SOD1 and be crucial for many biological processes. Isoform 1 which is localized to the endoplasmic reticulum membranes may specifically function in ER-associated protein degradation of misfolded proteins.

Subunit / interactions. Interacts with HSP70 (HSPA1A or HSPA1B). Interacts with HSPA8/Hsc70. Interacts with PSMA3 and most probably with the whole proteasomal complex.

Subcellular location. Cytoplasm. Nucleus Endoplasmic reticulum membrane.

Tissue specificity. More abundantly expressed in neocortex, cerebellum, spinal cord and retina where it is expressed by neuronal cells (at protein level). Detected at much lower level in non-neuronal tissues including kidney, lung, heart, skeletal muscle, spleen and testis (at protein level). Isoform 1 is more abundant in neocortex and cerebellum compared to isoform 2 (at protein level).

Post-translational modifications. Ubiquitinated by STUB1; does not lead to proteasomal degradation.

Disease relevance. Neuronopathy, distal hereditary motor, autosomal recessive 5 (HMNR5) [MIM:614881] 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. HMNR5 is characterized by young adult onset of slowly progressive distal muscle weakness and atrophy resulting in gait impairment and loss of reflexes. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The J domain is sufficient to interact with HSP70 (HSPA1A or HSPA1B) and activate its ATPase activity. The J domain is also required for the HSP70-mediated and ubiquitin-dependent proteasomal degradation of proteins like ATXN3. The J domain is required to reduce PRKN cytoplasmic aggregation. The UIM domains mediate interaction with ubiquitinated chaperone clients and with the proteasome. The UIM domains may have an opposite activity to the J domain, binding ubiquitinated proteins and protecting them from HSP70-mediated proteasomal degradation. The UIM domains are not required to reduce PRKN cytoplasmic aggregation.

Isoforms (2)

UniProt ID	Names	Canonical?
P25686-3	1, HSJ1b	yes
P25686-2	2, HSJ1a, DNAJB2a

RefSeq proteins (2): NP_001034639, NP_006727* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR003903	UIM_dom	Conserved_site
IPR018253	DnaJ_domain_CS	Conserved_site
IPR036869	J_dom_sf	Homologous_superfamily
IPR043183	DNJB2/6-like	Family

Pfam: PF00226

UniProt features (35 total): mutagenesis site 8, helix 4, compositionally biased region 3, modified residue 3, domain 3, splice variant 2, sequence variant 2, region of interest 2, initiator methionine 1, chain 1, lipid moiety-binding region 1, propeptide 1, sequence conflict 1, strand 1, turn 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2LGW	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P25686-F1	68.73	0.25

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 (4): 2, 311, 321, 321

Mutagenesis-validated functional residues (8):

Position	Phenotype
31–33	loss of interaction with hsp70 and loss of the ability to promote atxn3 proteasomal degradation.
31	probable loss of interaction with hsp70 and loss of the ability to reduce prkn aggregation.
219	loss of interaction with polyubiquitin chains, loss of interaction with psma3, and loss of the ability to protect atxn3
222	loss of interaction with polyubiquitin chains, loss of interaction with psma3, and loss of the ability to protect atxn3
262	loss of interaction with polyubiquitin chains, loss of interaction with psma3, and loss of the ability to protect atxn3
265	loss of interaction with polyubiquitin chains, loss of interaction with psma3, and loss of the ability to protect atxn3
321	loss of localization to the endoplasmic reticulum and relocalization to cytoplasm and nucleus.
324	no effect on localization to the endoplasmic reticulum membrane.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 335 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_REGULATION_OF_PROTEASOMAL_UBIQUITIN_DEPENDENT_PROTEIN_CATABOLIC_PROCESS, GOBP_REGULATION_OF_PROTEIN_BINDING, PAX4_01, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_NEGATIVE_REGULATION_OF_CELL_GROWTH, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, GOBP_GROWTH, GOBP_POSITIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS

GO Biological Process (18): protein folding (GO:0006457), response to unfolded protein (GO:0006986), negative regulation of cell population proliferation (GO:0008285), negative regulation of cell growth (GO:0030308), regulation of protein ubiquitination (GO:0031396), positive regulation of protein ubiquitination (GO:0031398), negative regulation of protein binding (GO:0032091), positive regulation of proteasomal ubiquitin-dependent protein catabolic process (GO:0032436), positive regulation of ATP-dependent activity (GO:0032781), regulation of protein localization (GO:0032880), ERAD pathway (GO:0036503), protein refolding (GO:0042026), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), neuron cellular homeostasis (GO:0070050), negative regulation of inclusion body assembly (GO:0090084), negative regulation of protein deubiquitination (GO:0090086), regulation of protein folding (GO:1903332), obsolete chaperone-mediated protein folding (GO:0061077)

GO Molecular Function (12): ATPase activator activity (GO:0001671), Hsp70 protein binding (GO:0030544), polyubiquitin modification-dependent protein binding (GO:0031593), ubiquitin protein ligase binding (GO:0031625), ubiquitin binding (GO:0043130), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), proteasome binding (GO:0070628), protein serine/threonine kinase binding (GO:0120283), ubiquitin-modified protein reader activity (GO:0140036), protein transporter activity (GO:0140318), protein binding (GO:0005515)

GO Cellular Component (11): proteasome complex (GO:0000502), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), inclusion body (GO:0016234), nuclear membrane (GO:0031965), perinuclear region of cytoplasm (GO:0048471), cytoplasmic side of endoplasmic reticulum membrane (GO:0098554), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
negative regulation of cellular process	2
protein ubiquitination	2
protein binding	2
ATP-dependent activity	2
proteasomal protein catabolic process	2
protein folding	2
intracellular membrane-bounded organelle	2
intracellular anatomical structure	2
organelle membrane	2
cellular process	1
protein maturation	1
response to topologically incorrect protein	1
cell population proliferation	1
regulation of cell population proliferation	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
regulation of protein modification by small protein conjugation or removal	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
regulation of protein binding	1
negative regulation of binding	1
regulation of proteasomal ubiquitin-dependent protein catabolic process	1
proteasome-mediated ubiquitin-dependent protein catabolic process	1
positive regulation of proteasomal protein catabolic process	1
positive regulation of ubiquitin-dependent protein catabolic process	1
regulation of ATP-dependent activity	1
positive regulation of molecular function	1
intracellular protein localization	1
regulation of localization	1
response to endoplasmic reticulum stress	1
response to chemical	1
ubiquitin-dependent protein catabolic process	1
cellular homeostasis	1
negative regulation of cellular component organization	1
inclusion body assembly	1
regulation of inclusion body assembly	1
protein deubiquitination	1

Protein interactions and networks

STRING

2651 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJB2	HSPB8	Q9UJY1	743
DNAJB2	HSPA8	P11142	684
DNAJB2	DNAJC6	O75061	666
DNAJB2	DNAJC13	O75165	664
DNAJB2	UBQLN1	Q9UMX0	646
DNAJB2	AHSA1	O95433	635
DNAJB2	HSPA1A	P08107	625
DNAJB2	GRPEL1	Q9HAV7	621
DNAJB2	BAG1	Q99933	612
DNAJB2	HSP90AB1	P08238	595
DNAJB2	DNAJA1	P31689	552
DNAJB2	STIP1	P31948	542
DNAJB2	HSPH1	Q92598	529
DNAJB2	SACS	Q9NZJ4	525
DNAJB2	HSPA4	P34932	520

IntAct

59 interactions, top by confidence:

A	B	Type	Score
GET4	GET3	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
MLF1	HAX1	psi-mi:“MI:0914”(association)	0.560
MLF1	DNAJB2	psi-mi:“MI:0915”(physical association)	0.560
DNAJB8	SCGB2A1	psi-mi:“MI:0914”(association)	0.530
DNAJB8	DNAJB6	psi-mi:“MI:0914”(association)	0.530
TIMP3	ZZEF1	psi-mi:“MI:0914”(association)	0.530
ERBB2	NDUFA4	psi-mi:“MI:0914”(association)	0.530
vif	HDAC3	psi-mi:“MI:0914”(association)	0.500
vif	DNAJB2	psi-mi:“MI:0914”(association)	0.460
UBQLN1	DNAJB2	psi-mi:“MI:0915”(physical association)	0.460
UBQLN1	DNAJB2	psi-mi:“MI:0403”(colocalization)	0.460
RPS27A	DNAJB2	psi-mi:“MI:0407”(direct interaction)	0.440
MLF2	DNAJB2	psi-mi:“MI:0915”(physical association)	0.400
DNAJB2		psi-mi:“MI:0915”(physical association)	0.400
DNAJB2	PSMD2	psi-mi:“MI:0915”(physical association)	0.400
	DNAJB2	psi-mi:“MI:0915”(physical association)	0.400
ECE1	DNAJB2	psi-mi:“MI:0915”(physical association)	0.370
SMAD4	DNAJB2	psi-mi:“MI:0915”(physical association)	0.370
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
SHLD3		psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350

BioGRID (174): DNAJB2 (Biochemical Activity), DNAJB2 (Affinity Capture-MS), DNAJB2 (Affinity Capture-MS), DNAJB2 (Affinity Capture-MS), UBB (Affinity Capture-MS), GLB1 (Affinity Capture-MS), TRO (Affinity Capture-MS), ATP7A (Affinity Capture-MS), ATP7B (Affinity Capture-MS), ARFGEF2 (Affinity Capture-MS), CTSA (Affinity Capture-MS), PJA1 (Affinity Capture-MS), FAM83H (Affinity Capture-MS), MORF4L1 (Affinity Capture-MS), ASNA1 (Affinity Capture-MS)

ESM2 similar proteins: G3H0N9, O13633, O35723, O54946, O75190, P25294, P25686, P35191, P39102, P48353, P53940, P78004, P87239, P97554, Q09912, Q0IIE8, Q0III6, Q0WTI8, Q10MW6, Q149L6, Q17438, Q28I38, Q4R7Y5, Q54ED3, Q58DR2, Q5F3Z5, Q5FWN8, Q5R6H3, Q5R8H0, Q5R9A4, Q5UP23, Q5XGU5, Q6AYU3, Q6P642, Q7ZXQ8, Q862Z4, Q8GWW8, Q8NHS0, Q8SRK0, Q8TA83

Diamond homologs: A0A0D1E2P6, A0A0P0VG31, A1BHL1, A1V9Q3, A3MA88, A4SFR5, A5EYE5, A5IIT4, A5ITA7, A6LJ63, A6QHC2, A6U251, A7X2Y0, A8EXP6, A8GMF8, A8GV67, A9IGC5, B0B7R0, B0BBX5, B0TYF3, B0VA24, B0VQ00, B1LCI2, B1YKT0, B2I2G6, B3CP03, B3EE31, B3QPW8, B4S9D0, B7GV08, B7I2B2, B7IFE0, B8DQW8, B9E6X0, B9KAB9, C4L424, O35723, O54946, O75190, O84345

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 63 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Defective CFTR causes cystic fibrosis	8	40.9×	8e-09
Regulation of activated PAK-2p34 by proteasome mediated degradation	5	32.4×	3e-05
NIK–>noncanonical NF-kB signaling	6	31.9×	4e-06
AMPK-induced ERAD and lysosome mediated degradation of PD-L1(CD274)	7	31.5×	4e-07
Vpu mediated degradation of CD4	5	30.9×	3e-05
Autodegradation of the E3 ubiquitin ligase COP1	5	30.9×	3e-05
Ubiquitin-dependent degradation of Cyclin D	5	30.9×	3e-05
Dectin-1 mediated noncanonical NF-kB signaling	6	30.1×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
transmembrane transport	5	15.3×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	10
Likely pathogenic	15
Uncertain significance	132
Likely benign	153
Benign	18

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1441902	NM_006736.6(DNAJB2):c.119_120del (p.Glu40fs)	Pathogenic
1452257	NM_006736.6(DNAJB2):c.204T>G (p.Tyr68Ter)	Pathogenic
1789094	NM_006736.6(DNAJB2):c.229+2T>A	Pathogenic
183041	NM_006736.6(DNAJB2):c.229+1G>A	Pathogenic
1895597	NM_006736.6(DNAJB2):c.118G>T (p.Glu40Ter)	Pathogenic
209147	NM_006736.6(DNAJB2):c.343G>T (p.Glu115Ter)	Pathogenic
217886	NM_006736.6(DNAJB2):c.352+1G>A	Pathogenic
246691	NM_006736.6(DNAJB2):c.620-1G>A	Pathogenic
254212	NM_001039550.2(DNAJB2):c.0_229+18del	Pathogenic
864789	NM_006736.6(DNAJB2):c.394C>T (p.Arg132Ter)	Pathogenic
1464699	NM_006736.6(DNAJB2):c.446-1G>A	Likely pathogenic
1709938	NM_006736.6(DNAJB2):c.65+1G>A	Likely pathogenic
183042	NM_006736.6(DNAJB2):c.14A>G (p.Tyr5Cys)	Likely pathogenic
243085	NM_006736.6(DNAJB2):c.310del (p.Arg104fs)	Likely pathogenic
2630116	NM_006736.6(DNAJB2):c.175+1G>C	Likely pathogenic
2696517	NM_006736.6(DNAJB2):c.445+1G>A	Likely pathogenic
2828827	NM_006736.6(DNAJB2):c.353-1G>C	Likely pathogenic
3376836	NM_006736.6(DNAJB2):c.65+1G>C	Likely pathogenic
3896843	NM_006736.6(DNAJB2):c.175+3A>T	Likely pathogenic
3896844	NM_006736.6(DNAJB2):c.352+1G>C	Likely pathogenic
3896845	NM_006736.6(DNAJB2):c.446-1G>C	Likely pathogenic
4073419	NM_006736.6(DNAJB2):c.159T>G (p.Tyr53Ter)	Likely pathogenic
4795860	NM_006736.6(DNAJB2):c.176-2A>G	Likely pathogenic
623377	NM_006736.6(DNAJB2):c.446-2A>G	Likely pathogenic
873313	NM_006736.6(DNAJB2):c.757G>A (p.Glu253Lys)	Likely pathogenic

SpliceAI

1620 predictions. Top by Δscore:

Variant	Effect	Δscore
2:219279796:A:AG	acceptor_gain	1.0000
2:219279797:G:GG	acceptor_gain	1.0000
2:219279894:AAGGC:A	donor_gain	1.0000
2:219279895:AGGC:A	donor_gain	1.0000
2:219279896:GGC:G	donor_gain	1.0000
2:219279896:GGCG:G	donor_gain	1.0000
2:219279897:GC:G	donor_gain	1.0000
2:219279897:GCG:G	donor_gain	1.0000
2:219279899:G:C	donor_loss	1.0000
2:219279899:G:GG	donor_gain	1.0000
2:219279900:T:A	donor_loss	1.0000
2:219280654:G:GT	donor_gain	1.0000
2:219280666:GCA:G	donor_gain	1.0000
2:219280672:G:GT	donor_gain	1.0000
2:219280684:GACA:G	donor_gain	1.0000
2:219280688:G:GG	donor_gain	1.0000
2:219281716:A:AG	acceptor_gain	1.0000
2:219281717:G:GG	acceptor_gain	1.0000
2:219281717:GA:G	acceptor_gain	1.0000
2:219281717:GAGC:G	acceptor_gain	1.0000
2:219281769:CAG:C	donor_loss	1.0000
2:219281770:AG:A	donor_loss	1.0000
2:219281771:GG:G	donor_loss	1.0000
2:219281773:T:A	donor_loss	1.0000
2:219281928:T:TA	acceptor_gain	1.0000
2:219281934:TCCA:T	acceptor_loss	1.0000
2:219281936:CAGG:C	acceptor_loss	1.0000
2:219281937:A:AG	acceptor_gain	1.0000
2:219281937:AG:A	acceptor_gain	1.0000
2:219281937:AGG:A	acceptor_loss	1.0000

AlphaMissense

2095 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:219280579:T:C	Y23H	1.000
2:219280592:C:A	A27D	1.000
2:219280595:T:C	L28P	1.000
2:219280600:T:A	W30R	1.000
2:219280600:T:C	W30R	1.000
2:219280603:C:A	H31N	1.000
2:219280603:C:G	H31D	1.000
2:219280604:A:G	H31R	1.000
2:219280605:C:A	H31Q	1.000
2:219280605:C:G	H31Q	1.000
2:219280614:A:C	K34N	1.000
2:219280614:A:T	K34N	1.000
2:219280648:T:C	F46L	1.000
2:219280649:T:C	F46S	1.000
2:219280649:T:G	F46C	1.000
2:219280650:T:A	F46L	1.000
2:219280650:T:G	F46L	1.000
2:219280679:T:A	L56Q	1.000
2:219280679:T:C	L56P	1.000
2:219279856:T:A	L8Q	0.999
2:219279889:T:A	I19N	0.999
2:219279893:G:C	K20N	0.999
2:219279893:G:T	K20N	0.999
2:219279897:G:C	A22P	0.999
2:219280579:T:G	Y23D	0.999
2:219280583:G:C	R24P	0.999
2:219280591:G:C	A27P	0.999
2:219280595:T:A	L28H	0.999
2:219280606:C:T	P32S	0.999
2:219280607:C:A	P32Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000101079 (2:219282229 G>C), RS1000230934 (2:219278177 T>C), RS1000283252 (2:219277846 G>A), RS1000703652 (2:219283775 G>C), RS1000938395 (2:219280963 A>G), RS1001137278 (2:219284068 A>C), RS1001233303 (2:219279415 C>A), RS1001701705 (2:219287067 T>A), RS1001732440 (2:219285227 C>T), RS1001753939 (2:219287316 G>C), RS1002239162 (2:219280884 T>A,C), RS1002668786 (2:219282686 A>G), RS1002698695 (2:219277400 A>C,G), RS1002731550 (2:219277804 C>A), RS1003266824 (2:219281702 TG>T)

Disease associations

OMIM: gene MIM:604139 | disease phenotypes: MIM:614881, MIM:118220, MIM:605726, MIM:302800, MIM:302900

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2T	Definitive	Autosomal recessive
neuronopathy, distal hereditary motor, autosomal recessive 5	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease axonal type 2T	Definitive	AR

Mondo (6): neuronopathy, distal hereditary motor, autosomal recessive 5 (MONDO:0013947), Charcot-Marie-Tooth disease (MONDO:0015626), autosomal recessive distal spinal muscular atrophy 2 (MONDO:0011585), (MONDO:0014866), Charcot-Marie-Tooth disease X-linked dominant 1 (MONDO:0010549), Charcot-Marie-Tooth disease type 2 (MONDO:0018993)

Orphanet (6): Young adult-onset distal hereditary motor neuropathy (Orphanet:314485), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Distal hereditary motor neuropathy, Jerash type (Orphanet:139552), DNAJB2-related Charcot-Marie-Tooth disease type 2 (Orphanet:443950), X-linked Charcot-Marie-Tooth disease type 1 (Orphanet:101075), Autosomal dominant Charcot-Marie-Tooth disease type 2 (Orphanet:64746)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001618	Dysphonia
HP:0001761	Pes cavus
HP:0002460	Distal muscle weakness
HP:0002936	Distal sensory impairment
HP:0003677	Slowly progressive
HP:0007269	Spinal muscular atrophy
HP:0008944	Distal lower limb amyotrophy
HP:0009027	Foot dorsiflexor weakness
HP:0011462	Young adult onset

GWAS associations

0 associations (top):

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
C564446	Charcot-Marie-Tooth Peroneal Muscular Atrophy and Friedreich Ataxia, Combined (supp.)
C535715	Spinal muscular atrophy, Jerash type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cisplatin	affects expression, affects cotreatment, decreases expression, increases expression	4
Cyclosporine	decreases expression, increases expression	4
Benzo(a)pyrene	decreases methylation, increases expression, affects methylation	3
Aflatoxin B1	affects expression, decreases methylation, increases expression	3
Cadmium Chloride	decreases expression, increases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
beta-N-methylamino-L-alanine	increases expression	1
chloroacetaldehyde	increases expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
dinophysistoxin 1	increases expression	1
oxidized-L-alpha-1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine	increases reaction, affects expression	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
abrine	increases expression	1
darinaparsin	increases expression	1
eprenetapopt	increases expression	1
jinfukang	decreases expression, affects cotreatment	1
PCI 5002	increases expression, affects cotreatment	1
Decitabine	affects expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT01289704	PHASE2/PHASE3	UNKNOWN	Treadmill, Stretching and Proprioceptive Exercise (TreSPE) Rehabilitation Program for Charcot-Marie-Tooth Neuropathy Type 1A (CMT1A)
NCT00541164	PHASE1/PHASE2	COMPLETED	Effects of Coenzyme Q10 on Charcot-Marie-Tooth Disease
NCT05361031	PHASE1/PHASE2	COMPLETED	The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A)
NCT07223632	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Treatment of Charcot-Marie-Tooth Disease, Axonal, Type 2S (CMT2S) in an Individual Patient
NCT00149045	Not specified	COMPLETED	Follow up and Observation of Charcot Marie Tooth Disease in Families
NCT01193075	Not specified	RECRUITING	Natural History Evaluation of Charcot Marie Tooth Disease (CMT) Types CMT1B, CMT2A, CMT4A, CMT4C, and Others
NCT01203085	Not specified	COMPLETED	Development of Charcot Marie Tooth Disease (CMT) Pediatric Scale for Children With CMT
NCT01455623	Not specified	COMPLETED	Development and Validation of a Disability Severity Index for CMT
NCT01918826	Not specified	UNKNOWN	Evaluation of the Analgesic Efficiency of the Transcutaneous Neurostimulation in the Charcot Syndrome Marie Tooth on the Pains of Lower Limbs
NCT02001038	Not specified	COMPLETED	Survey of Current Management of Orthopaedic Complications in CMT Patients
NCT02011204	Not specified	COMPLETED	Study of Electrical Impedance Myography (EIM) in ALS
NCT02194010	Not specified	COMPLETED	Disability Severity Scale (DSI) and Hereditary Motor and Sensory Neuropathy Overall Disability Scale (HMSN-R-ODS)
NCT02429947	Not specified	COMPLETED	An Analysis of the Symptomatic Domains Most Relevant to Charcot Marie Tooth Neuropathy (CMT) Patients
NCT02532244	Not specified	COMPLETED	Genetics of Pediatric-Onset Motor Neuron and Neuromuscular Diseases
NCT02699190	Not specified	COMPLETED	LeukoSEQ: Whole Genome Sequencing as a First-Line Diagnostic Tool for Leukodystrophies
NCT02788734	Not specified	COMPLETED	Patient Reported Outcomes Measures (PROM) in Carpal Tunnel Therapies in Patients With Inherited Neuropathies
NCT02979145	Not specified	UNKNOWN	Charcot-Marie-Tooth Disease (CMT) Infant Scale (INC-6611)
NCT03047369	Not specified	RECRUITING	The Myelin Disorders Biorepository Project
NCT03460951	Not specified	COMPLETED	Diffusion Tensor Imaging in Chronic Inflammatory Demyelinating Polyneuropathy (PIDC)
NCT03715283	Not specified	COMPLETED	Change in MUNIX in Patients With CMT1A Undergoing a Home Ankle Strengthening Program Versus Standard of Care
NCT03782883	Not specified	COMPLETED	The Impact of Charcot-Marie-Tooth Disease in the Real World
NCT03810508	Not specified	TERMINATED	A Natural History Study of Charcot-Marie-Tooth 4J (CMT4J)
NCT03966287	Not specified	COMPLETED	Analysis of Pain and Quality of Life in Patients With Charcot-Marie-Tooth Neuropathy (CMT)
NCT04010188	Not specified	RECRUITING	A Registered Cohort Study on Charcot-Marie-Tooth Disease
NCT04283175	Not specified	COMPLETED	Validation Study of Posturology Platforms for Evaluating Postural Control of Hemiparetic and Neuro-muscular Patients
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument
NCT04786522	Not specified	COMPLETED	Irisin Levels in Patients With Charcot-Marie-Tooth (CMT) Disease
NCT04967716	Not specified	UNKNOWN	Genetics of Charcot-Marie-Tooth Dystrophy and Related Diseases
NCT04980807	Not specified	COMPLETED	Observational Study of Neuromuscular Function in CMT Type 1&2 and Healthy Controls
NCT05011006	Not specified	NOT_YET_RECRUITING	NT-3 Levels and Function in Individuals With CMT