DNAJB6

Summary

DNAJB6 (DnaJ heat shock protein family (Hsp40) member B6, HGNC:14888) is a protein-coding gene on chromosome 7q36.3, encoding DnaJ homolog subfamily B member 6 (O75190). Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70. It is a selective cancer dependency (DepMap: 29.2% of cell lines).

This gene encodes a member of the DNAJ protein family. DNAJ family members are characterized by a highly conserved amino acid stretch called the ‘J-domain’ and function as one of the two major classes of molecular chaperones involved in a wide range of cellular events, such as protein folding and oligomeric protein complex assembly. This family member may also play a role in polyglutamine aggregation in specific neurons. Alternative splicing of this gene results in multiple transcript variants; however, not all variants have been fully described.

Source: NCBI Gene 10049 — RefSeq curated summary.

At a glance

• Gene–disease (curated): muscular dystrophy, limb-girdle, autosomal dominant (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 4
• Clinical variants (ClinVar): 538 total — 17 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 29
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 29.2% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_058246

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14888
Approved symbol	DNAJB6
Name	DnaJ heat shock protein family (Hsp40) member B6
Location	7q36.3
Locus type	gene with protein product
Status	Approved
Aliases	MRJ
Ensembl gene	ENSG00000105993
Ensembl biotype	protein_coding
OMIM	611332
Entrez	10049

Gene structure

Transcript identifiers

Ensembl transcripts: 51 — 43 protein_coding, 3 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000262177, ENST00000412557, ENST00000417758, ENST00000429029, ENST00000437030, ENST00000439402, ENST00000441291, ENST00000441561, ENST00000443280, ENST00000453383, ENST00000459889, ENST00000465908, ENST00000468928, ENST00000486083, ENST00000486247, ENST00000487480, ENST00000488001, ENST00000634080, ENST00000867734, ENST00000867735, ENST00000867736, ENST00000867737, ENST00000867738, ENST00000867739, ENST00000867740, ENST00000867741, ENST00000867742, ENST00000911732, ENST00000911733, ENST00000911734, ENST00000911735, ENST00000911736, ENST00000911737, ENST00000911738, ENST00000911739, ENST00000956617, ENST00000956618, ENST00000956619, ENST00000956620, ENST00000956621, ENST00000956622, ENST00000956623, ENST00000956624, ENST00000956625, ENST00000956626, ENST00000956627, ENST00000956628, ENST00000956629, ENST00000956630, ENST00000956631, ENST00000956632

RefSeq mRNA: 3 — MANE Select: NM_058246 NM_001363676, NM_005494, NM_058246

CCDS: CCDS47755, CCDS5946, CCDS87571

Canonical transcript exons

ENST00000262177 — 10 exons

Exon	Start	End
ENSE00001705365	157337004	157337144
ENSE00001931810	157416016	157417439
ENSE00003486218	157382246	157382377
ENSE00003519262	157384867	157385008
ENSE00003572534	157409795	157410001
ENSE00003592526	157367373	157367483
ENSE00003595878	157358547	157358637
ENSE00003612095	157385541	157385611
ENSE00003648894	157363161	157363270
ENSE00003681432	157366502	157366561

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 99.19.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.1451 / max 516.7301, expressed in 1815 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82289	27.4140	1814
82290	4.3417	1307
82291	0.8188	382
82293	0.3234	125
82288	0.2389	85
82294	0.0083	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.99	gold quality
ganglionic eminence	UBERON:0004023	98.68	gold quality
gastrocnemius	UBERON:0001388	98.59	gold quality
muscle of leg	UBERON:0001383	98.51	gold quality
skin of abdomen	UBERON:0001416	98.48	gold quality
skin of leg	UBERON:0001511	98.42	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.42	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.16	gold quality
popliteal artery	UBERON:0002250	98.11	gold quality
tibial artery	UBERON:0007610	98.11	gold quality
ventricular zone	UBERON:0003053	98.09	gold quality
right testis	UBERON:0004534	98.05	gold quality
muscle organ	UBERON:0001630	98.00	gold quality
skeletal muscle organ	UBERON:0014892	98.00	gold quality
monocyte	CL:0000576	97.96	gold quality
left testis	UBERON:0004533	97.96	gold quality
aorta	UBERON:0000947	97.94	gold quality
ascending aorta	UBERON:0001496	97.94	gold quality
thoracic aorta	UBERON:0001515	97.94	gold quality
right coronary artery	UBERON:0001625	97.87	gold quality
artery	UBERON:0001637	97.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.78	gold quality
mononuclear cell	CL:0000842	97.77	gold quality
descending thoracic aorta	UBERON:0002345	97.76	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.72	gold quality
lower esophagus	UBERON:0013473	97.71	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.71	gold quality
leukocyte	CL:0000738	97.69	gold quality
left coronary artery	UBERON:0001626	97.69	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1724.64
E-GEOD-124263	yes	1369.64
E-CURD-112	no	3.19
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFATC3

miRNA regulators (miRDB)

38 targeting DNAJB6, 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-4668-3P	100.00	68.74	2635
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-7158-5P	99.25	67.95	796
HSA-MIR-196A-3P	99.19	67.34	1204
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-4725-5P	98.67	65.42	628
HSA-MIR-504-5P	98.67	65.40	631
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-5691	98.23	67.02	1335
HSA-MIR-6805-3P	98.23	67.02	1334

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 29.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• MRJ has a relevant functional role in neurons. (PMID:11896048)
• Role of Hsp40 co-chaperone Hdj-1 in CFTR turnover with HSP70 (PMID:12069690)
• NFATc3 is negatively regulated by class II histone deacetylases through the DnaJ (heat shock protein-40) superfamily member Mrj (PMID:16260608)
• msj-1 gene might be conserved among vertebrates and might exert fundamental functions in reproduction. (PMID:18184612)
• Large isoform of MRJ(L), DNAJB6, is a nuclear protein that is lost in breast cancer, that regulates several key players in tumor formation and metastasis, and that is functionally able to retard tumor growth. (PMID:18328103)
• DnaJB6 is necessary for translocation of Slfn1 into the nucleus, where Slfn1 down-regulates cyclin D1, induces cell-cycle arrest and programmes a quiescent state of T-cells (PMID:18373498)
• we report the up-regulation of Mrj protein in M-phase of HeLa cells implicating its role in mitosis related activities. (PMID:19002655)
• DNAJB6b and DNAJB8 are superior suppressors of aggregation and toxicity of disease-associated polyglutamine proteins. (PMID:20159555)
• the interaction between urokinase receptor and heat shock protein MRJ enhances cell adhesion (PMID:20372789)
• DNAJB6 induces degradation of beta-catenin and causes partial reversal of mesenchymal phenotype (PMID:20522561)
• Mutations within the Pro96Arg domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. (PMID:22334415)
• studied 9 Limb-girdle muscular dystrophy type 1D affected families from Finland, the United States and Italy and identified 4 dominant missense mutations leading to p.Phe93Leu or p.Phe89Ile changes in the co-chaperone DNAJB6 (PMID:22366786)
• A novel regulatory mechanism for DNAJB6-mediated DKK1 transcriptional up-regulation might influence epithelial-mesenchymal transition. (PMID:22455953)
• MRJ (short form) shows nuclear localization signal independent nuclear localization in response to heat shock and hypoxia. (PMID:22504047)
• miR-632 is a potentially important epigenetic regulator of DNAJB6, which contributes to the downregulation of DNAJB6 and plays a supportive role in malignant progression (PMID:22710984)
• the relative expression levels of DNAJB6 isoforms may play a key role in regulating the cellular localization of UL70, leading to modulation of HCMV DNA synthesis and lytic infection. (PMID:23133382)
• we detected cytoplasmic accumulations associated with chaperone-assisted selective autophagy together with intranuclear accumulations of DNAJB6 and HSPB8. This is the first report of Asian patients with limb-girdle muscular dystrophy type 1D (PMID:23394708)
• The mechanism of DNAJB6 and DNAJB8 is suppression of polyQ protein aggregation by directly binding the polyQ tract. (PMID:23612975)
• have previously reported clinical, genetic and molecular pathomechanistic findings in DNAJB6 mutated LGMD1D (PMID:23865856)
• DNAJB6 is a peptide-binding chaperone that can interact with polyQ peptides that are incompletely degraded by and released from the proteasome. (PMID:23904097)
• We identified DNAJ/HSP40B6 as a potential negative regulator of HIV-1 replication in our genetic screens. (PMID:24047968)
• A 56-year-old woman, like 3 other family members, becomes symptomatic in childhood with slowly progressive limb-girdle muscle weakness, normal serum creatine kinase (CK) values, and myopathic electromyographic findings. (PMID:24170373)
• using exome sequencing, study identified a mutation in DNAJB6 in a family with limb-girdle muscular dystrophy type 1D; work further confirms the causative role of DNAJB6 mutations in limb-girdle muscular dystrophy type 1D (PMID:24594375)
• DNAJB6 G/F domain mutants disrupt the processing of nuclear TDP-43 stress granules in mammalian cells. (PMID:24920671)
• There was a positive correlation between DNAJB6 and IQGAP1 expression. (PMID:25044025)
• Findings suggest a novel function of HSP70/MRJ/uPAR complex in cell adhesion, invasion and migration, and may provide more understanding in the mechanisms of uPAR-mediated cancer metastasis. (PMID:25175595)
• DNAJB6 interacts with growing amyloid-beta 42 (Abeta42) aggregates, which leads to sub-stoichiometric inhibition of amyloid formation (PMID:25217638)
• Geneticanalysis indicated a heterozygous missense mutation of c.279C>G (PMID:25306414)
• This study showed that Complete loss of the DNAJB6 G/F domain and novel missense mutations cause distal-onset DNAJB6 myopathy. (PMID:26205529)
• DNAJB6a reduces AKT signaling, and DNAJB6 expression in cancer cells reduces their proliferation and growth of xenograft esophageal squamous cell tumors in mice. (PMID:26302489)
• DNAJB6 mutations p.F91I and p.F91L show a significant reduction of the anti-aggregation function compared to the wild-type and p.F93L mutation (PMID:26338452)
• LGMD1D mutations in DNAJB6 disrupt its sarcoplasmic function suggesting a role for DNAJB6b in Z-disc organization and stress granule kinetics. (PMID:26362252)
• Functional study using zebrafish embryos demonstrated that p.Phe91Leu elicits more severe muscle defects than the reported p.Phe93Leu and p.Pro96Arg mutations (PMID:26371419)
• DnaJB6-protected yeast cells from polyglutamine toxicity and cured yeast of both [URE3] prions and weak variants of [PSI(+)] prions but not strong [PSI(+)] prions (PMID:26702057)
• The results indicate both genetic and physical interactions between disease-linked RNA-binding proteinss and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of adult-onset inherited myopathies initiated by mutations in hnRNPA2B1 and DNAJB6. (PMID:26744327)
• mRNA levels of HSP family members (HSP70B’, HSP72, HSP40/DNAJ, and HSP20/CRYAB) are upregulated by the intracellular MMP3 overload. (PMID:27206651)
• DNAJB6 is a central and versatile player in the protein aggregation and degradation system.DNAJB6 protein keeps Parkin C289G mutant protein in a soluble, degradation-competent form. (PMID:27713507)
• This study expands the molecular spectrum of DNAJB6 mutations and also emphasizes the pathogenic role of DNAJB6 dysfunction in distal-onset myopathy. (PMID:28233300)
• the cytoprotective effects of DNAJB6(S) may be mediated, at least in part, by the mitochondrial pathway of apoptosis. (PMID:28280525)
• Expression of the heat shock protein DNAJB6/MRJ was elevated in neutrophils and lymphocytes of patients with atopic dermatitis compared with healthy donors. The highest level of the DNAJB6/MRJ protein was found to be in neutrophils at acute phase of severe atopic dermatitis and gradually decline as continue to the disease. (PMID:29244458)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
mus_musculus	Dnajb6	ENSMUSG00000029131
rattus_norvegicus	Dnajb6	ENSRNOG00000010353
rattus_norvegicus	Dnajb6-ps10	ENSRNOG00000017884
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), DNAJB9 (ENSG00000128590), DNAJB1 (ENSG00000132002), DNAJB2 (ENSG00000135924), DNAJB5 (ENSG00000137094), DNAJB12 (ENSG00000148719), DNAJB4 (ENSG00000162616), DNAJB14 (ENSG00000164031), DNAJB7 (ENSG00000172404), DNAJB8 (ENSG00000179407), DNAJB13 (ENSG00000187726)

Protein

Protein identifiers

DnaJ homolog subfamily B member 6 — O75190 (reviewed: O75190)

Alternative names: HHDJ1, Heat shock protein J2, MRJ, MSJ-1

All UniProt accessions (10): O75190, A0A0J9YX62, C9J2C4, C9J2P2, C9JB42, C9JDR7, C9JDX6, C9JN01, E9PH18, F8WCZ4

UniProt curated annotations — full annotation on UniProt →

Function. Has a stimulatory effect on the ATPase activity of HSP70 in a dose-dependent and time-dependent manner and hence acts as a co-chaperone of HSP70. Plays an indispensable role in the organization of KRT8/KRT18 filaments. Acts as an endogenous molecular chaperone for neuronal proteins including huntingtin. Suppresses aggregation and toxicity of polyglutamine-containing, aggregation-prone proteins. Also reduces cellular toxicity and caspase-3 activity. Isoform B but not isoform A inhibits huntingtin aggregation.

Subunit / interactions. Homooligomer. Interacts with BAG3, HSPB8 and STUB1. Interacts with ALKBH1. Interacts with HSP70, KRT18 and PTTG. Interacts with histone deacetylases HDAC4, HDAC6, and SIRT2, HDAC activity is required for antiaggregation.

Subcellular location. Cytoplasm. Perinuclear region. Nucleus. Myofibril. Sarcomere. Z line.

Tissue specificity. Widely expressed. Highest levels in testis and brain, and lower levels in heart, spleen, intestine, ovary, placenta, lung, kidney, pancreas, thymus, prostate, skeletal muscle, liver and leukocytes. In testis, expressed in germ cells in the earlier stages of differentiation pathway as well as in spermatids. In brain, expressed at a higher level in hippocampus and thalamus and a lower level in amygdala, substantia nigra, corpus callosum and caudate nucleus.

Disease relevance. Muscular dystrophy, limb-girdle, autosomal dominant 1 (LGMDD1) [MIM:603511] An autosomal dominant myopathy characterized by adult onset of proximal muscle weakness, beginning in the hip girdle region and later progressing to the shoulder girdle region. The disease is caused by variants affecting the gene represented in this entry. There is evidence that LGMDD1 is caused by dysfunction of isoform B.

Domain organisation. The antiaggregation activity of isoform B resides in the serine-rich region and the C-terminus.

Isoforms (4)

UniProt ID	Names	Canonical?
O75190-1	A	yes
O75190-2	B
O75190-3	C, a
O75190-4	D

RefSeq proteins (3): NP_001350605, NP_005485, NP_490647* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00226

UniProt features (32 total): helix 6, strand 5, splice variant 4, sequence variant 4, turn 3, region of interest 3, sequence conflict 2, modified residue 2, initiator methionine 1, chain 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6U3R	SOLUTION NMR
6U3S	SOLUTION NMR
7JSQ	SOLUTION NMR
7QBY	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75190-F1	64.04	0.10

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 (2): 135, 277

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-3371453	Regulation of HSF1-mediated heat shock response
R-HSA-3371511	HSF1 activation
R-HSA-3371568	Attenuation phase
R-HSA-3371571	HSF1-dependent transactivation

MSigDB gene sets: 357 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_INTERMEDIATE_FILAMENT_BASED_PROCESS, GOBP_INTERMEDIATE_FILAMENT_ORGANIZATION, TGCACTT_MIR519C_MIR519B_MIR519A, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, CACCAGC_MIR138, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GARGALOVIC_RESPONSE_TO_OXIDIZED_PHOSPHOLIPIDS_BLUE_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_HEAT, ATGTTAA_MIR302C, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_CELL_DIFFERENTIATION_INVOLVED_IN_EMBRYONIC_PLACENTA_DEVELOPMENT

GO Biological Process (14): protein folding (GO:0006457), actin cytoskeleton organization (GO:0030036), extracellular matrix organization (GO:0030198), regulation of protein localization (GO:0032880), protein localization to nucleus (GO:0034504), intermediate filament organization (GO:0045109), negative regulation of DNA-templated transcription (GO:0045892), nervous system process (GO:0050877), chorio-allantoic fusion (GO:0060710), syncytiotrophoblast cell differentiation involved in labyrinthine layer development (GO:0060715), chorion development (GO:0060717), negative regulation of inclusion body assembly (GO:0090084), regulation of cellular response to heat (GO:1900034), obsolete chaperone-mediated protein folding (GO:0061077)

GO Molecular Function (9): ATPase activator activity (GO:0001671), DNA binding (GO:0003677), Hsp70 protein binding (GO:0030544), heat shock protein binding (GO:0031072), identical protein binding (GO:0042802), protein folding chaperone (GO:0044183), obsolete unfolded protein binding (GO:0051082), protein-folding chaperone binding (GO:0051087), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), Z disc (GO:0030018), perinuclear region of cytoplasm (GO:0048471)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cellular response to heat stress	3
HSF1-dependent transactivation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein binding	3
cytoplasm	2
cellular process	1
protein maturation	1
cytoskeleton organization	1
actin filament-based process	1
extracellular structure organization	1
external encapsulating structure organization	1
intracellular protein localization	1
regulation of localization	1
protein localization to organelle	1
intermediate filament cytoskeleton organization	1
supramolecular fiber organization	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
system process	1
labyrinthine layer morphogenesis	1
cell-cell adhesion	1
cell differentiation involved in embryonic placenta development	1
labyrinthine layer development	1
extraembryonic membrane development	1
negative regulation of cellular component organization	1
inclusion body assembly	1
regulation of inclusion body assembly	1
cellular response to heat	1
regulation of cellular response to stress	1
ATP-dependent activity	1
molecular function activator activity	1
nucleic acid binding	1
heat shock protein binding	1
protein-folding chaperone binding	1
molecular_function	1
protein folding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
I band	1

Protein interactions and networks

STRING

2836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJB6	HSPA4	P34932	908
DNAJB6	HSPA8	P11142	867
DNAJB6	BAG3	O95817	862
DNAJB6	HSPB8	Q9UJY1	750
DNAJB6	GRPEL1	Q9HAV7	736
DNAJB6	HSPA1A	P08107	711
DNAJB6	STUB1	Q9UNE7	702
DNAJB6	MYOT	Q9UBF9	685
DNAJB6	HSP90AA1	P07900	660
DNAJB6	HDAC4	P56524	654
DNAJB6	SNCA	P37840	578
DNAJB6	MLF1	P58340	552
DNAJB6	RBM17	Q96I25	545
DNAJB6	APP	P05067	536
DNAJB6	CRYAB	P02511	535

IntAct

231 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
DNAJB6	KRT18	psi-mi:“MI:0915”(physical association)	0.620
DNAJB6	KRT18	psi-mi:“MI:0914”(association)	0.620
KRT18	DNAJB6	psi-mi:“MI:0915”(physical association)	0.620
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
CBLB	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
IK	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
RPP25	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
SPATA22	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
ASCL4	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
MAGEC3	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
FAM117B	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
ZSCAN1	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
CFAP100	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560
ZNF829	DNAJB6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (451): DNAJB6 (Affinity Capture-Western), DNAJB6 (Affinity Capture-Western), DNAJB6 (Biochemical Activity), DNAJB6 (Affinity Capture-MS), DNAJB2 (Affinity Capture-MS), C12orf45 (Affinity Capture-MS), BAG3 (Affinity Capture-Western), HSPB8 (Affinity Capture-Western), STUB1 (Affinity Capture-Western), Bag3 (Co-localization), Hspb8 (Co-localization), Stub1 (Co-localization), DNAJB6 (Affinity Capture-MS), DNAJB6 (Proximity Label-MS), DNAJB6 (Proximity Label-MS)

ESM2 similar proteins: C0HK94, C0HK95, E9PV24, J7M3T1, J7M799, M9MRD1, O13858, O54946, O75190, P02671, P02672, P0CU45, P0CU46, P0CU47, P0CU48, P0CU50, P14448, P20240, P30933, P36228, P46335, P78890, P87346, Q04757, Q09231, Q24546, Q4WUL0, Q4X212, Q55FC2, Q55FC3, Q55FC4, Q55FC5, Q5F3Z5, Q5R8H0, Q6AYU3, Q6CVS3, Q6FJC7, Q6FX33, Q7Z6W7, Q90501

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 181 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
Translocation of SLC2A4 (GLUT4) to the plasma membrane	7	10.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	2
Uncertain significance	253
Likely benign	150
Benign	52

Top pathogenic / likely-pathogenic (19)

Variant ID	HGVS	Classification
1322758	NM_058246.4(DNAJB6):c.271T>C (p.Phe91Leu)	Pathogenic
152725	GRCh38/hg38 7q36.3(chr7:155574967-159335866)x1	Pathogenic
1705937	GRCh37/hg19 7q36.3(chr7:155389460-157960969)x1	Pathogenic
2136635	NM_058246.4(DNAJB6):c.287C>T (p.Pro96Leu)	Pathogenic
225174	NM_058246.4(DNAJB6):c.298T>G (p.Phe100Val)	Pathogenic
225175	NM_058246.4(DNAJB6):c.271T>A (p.Phe91Ile)	Pathogenic
225176	NM_058246.4(DNAJB6):c.273C>G (p.Phe91Leu)	Pathogenic
225177	NM_058246.4(DNAJB6):c.346+5G>A	Pathogenic
3062957	GRCh37/hg19 7q36.3(chr7:155607058-159119707)x1	Pathogenic
30904	NM_058246.4(DNAJB6):c.277T>C (p.Phe93Leu)	Pathogenic
30905	NM_058246.4(DNAJB6):c.287C>G (p.Pro96Arg)	Pathogenic
31529	NM_058246.4(DNAJB6):c.279C>G (p.Phe93Leu)	Pathogenic
31530	NM_058246.4(DNAJB6):c.279C>A (p.Phe93Leu)	Pathogenic
31531	NM_058246.4(DNAJB6):c.265T>A (p.Phe89Ile)	Pathogenic
443710	GRCh37/hg19 7q36.3(chr7:156320289-159119707)x3	Pathogenic
4737597	NM_058246.4(DNAJB6):c.290ATG[1] (p.Asp98del)	Pathogenic
686940	GRCh37/hg19 7q36.3(chr7:156629234-159119707)x1	Pathogenic
253366	GRCh37/hg19 7q36.3(chr7:156431577-157598312)x1	Likely pathogenic
830317	NM_058246.4(DNAJB6):c.236G>A (p.Gly79Asp)	Likely pathogenic

SpliceAI

3712 predictions. Top by Δscore:

Variant	Effect	Δscore
7:157337078:GCT:G	donor_gain	1.0000
7:157358633:AAGGC:A	donor_gain	1.0000
7:157358634:AGGC:A	donor_gain	1.0000
7:157358635:GGCG:G	donor_gain	1.0000
7:157358635:GGCGT:G	donor_loss	1.0000
7:157358636:GC:G	donor_gain	1.0000
7:157358636:GCGT:G	donor_loss	1.0000
7:157358638:G:GA	donor_loss	1.0000
7:157358638:G:GG	donor_gain	1.0000
7:157358639:TAA:T	donor_loss	1.0000
7:157363158:A:AG	acceptor_gain	1.0000
7:157363158:AAG:A	acceptor_loss	1.0000
7:157363159:A:AG	acceptor_gain	1.0000
7:157363159:AGAT:A	acceptor_loss	1.0000
7:157363160:G:GA	acceptor_gain	1.0000
7:157363160:GA:G	acceptor_gain	1.0000
7:157363160:GAT:G	acceptor_gain	1.0000
7:157363160:GATA:G	acceptor_gain	1.0000
7:157363160:GATAT:G	acceptor_gain	1.0000
7:157363266:GGATG:G	donor_gain	1.0000
7:157363267:GATG:G	donor_gain	1.0000
7:157363267:GATGG:G	donor_gain	1.0000
7:157363269:TGGTG:T	donor_loss	1.0000
7:157363270:GGTG:G	donor_loss	1.0000
7:157363271:G:GG	donor_gain	1.0000
7:157363271:GTG:G	donor_loss	1.0000
7:157363272:T:A	donor_loss	1.0000
7:157363273:GAGT:G	donor_loss	1.0000
7:157366498:TTA:T	acceptor_loss	1.0000
7:157366500:A:AG	acceptor_gain	1.0000

AlphaMissense

2124 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:157358595:T:A	L8Q	1.000
7:157358632:A:C	K20N	1.000
7:157358632:A:T	K20N	1.000
7:157363162:T:C	Y23H	1.000
7:157363166:G:C	R24P	1.000
7:157363174:G:A	A27T	1.000
7:157363175:C:A	A27E	1.000
7:157363178:T:A	L28Q	1.000
7:157363178:T:C	L28P	1.000
7:157363183:T:A	W30R	1.000
7:157363183:T:C	W30R	1.000
7:157363186:C:A	H31N	1.000
7:157363186:C:G	H31D	1.000
7:157363187:A:G	H31R	1.000
7:157363188:T:A	H31Q	1.000
7:157363188:T:G	H31Q	1.000
7:157363189:C:T	P32S	1.000
7:157363190:C:A	P32Q	1.000
7:157363192:G:C	D33H	1.000
7:157363193:A:G	D33G	1.000
7:157363193:A:T	D33V	1.000
7:157363195:A:C	K34Q	1.000
7:157363195:A:G	K34E	1.000
7:157363196:A:T	K34I	1.000
7:157363197:A:C	K34N	1.000
7:157363197:A:T	K34N	1.000
7:157363231:T:C	F46L	1.000
7:157363231:T:G	F46V	1.000
7:157363232:T:C	F46S	1.000
7:157363232:T:G	F46C	1.000

dbSNP variants (sampled 300 via entrez): RS1000012949 (7:157373190 G>T), RS1000060273 (7:157408589 G>A,C), RS1000063256 (7:157380336 G>A,C), RS1000074011 (7:157389869 C>G,T), RS1000165358 (7:157370434 G>A), RS1000173723 (7:157397587 T>C), RS1000220193 (7:157402448 C>T), RS1000230206 (7:157385212 T>C), RS1000243798 (7:157346918 C>A,G,T), RS1000256128 (7:157366123 G>A), RS1000294032 (7:157410134 G>A), RS1000333779 (7:157406071 C>T), RS1000336218 (7:157401929 G>A), RS1000378877 (7:157375038 T>A,C), RS1000384555 (7:157370858 G>A,C)

Disease associations

OMIM: gene MIM:611332 | disease phenotypes: MIM:603511, MIM:142945, MIM:130000, MIM:130010, MIM:168600

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
muscular dystrophy, limb-girdle, autosomal dominant	Definitive	AD

Mondo (7): autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) (MONDO:0021018), holoprosencephaly 3 (MONDO:0007733), microcephaly (MONDO:0001149), muscular dystrophy, limb-girdle, autosomal dominant (MONDO:0015151), Ehlers-Danlos syndrome, classic type, 1 (MONDO:0019567), Ehlers-Danlos syndrome, classic type, 2 (MONDO:0019568), late-onset Parkinson disease (MONDO:0008199)

Orphanet (7): DNAJB6-related limb-girdle muscular dystrophy D1 (Orphanet:34516), Holoprosencephaly (Orphanet:2162), Autosomal dominant limb-girdle muscular dystrophy (Orphanet:102014), Classical Ehlers-Danlos syndrome (Orphanet:287), OBSOLETE: Ehlers-Danlos syndrome type 2 (Orphanet:90318), Hereditary late-onset Parkinson disease (Orphanet:411602), OBSOLETE: Ehlers-Danlos syndrome type 1 (Orphanet:90309)

HPO phenotypes

29 total (30 of 29 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001260	Dysarthria
HP:0001283	Bulbar palsy
HP:0001371	Flexion contracture
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002505	Loss of ambulation
HP:0002515	Waddling gait
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003324	Generalized muscle weakness
HP:0003326	Myalgia
HP:0003391	Gowers sign
HP:0003547	Shoulder girdle muscle weakness
HP:0003551	Difficulty climbing stairs
HP:0003555	Muscle fiber splitting
HP:0003557	Increased variability in muscle fiber diameter
HP:0003560	Muscular dystrophy
HP:0003677	Slowly progressive
HP:0003715	Myofibrillar myopathy
HP:0003749	Pelvic girdle muscle weakness
HP:0003805	Rimmed vacuoles
HP:0004303	Abnormal muscle fiber morphology
HP:0009046	Difficulty running
HP:0010548	Percussion myotonia
HP:0010628	Facial palsy
HP:0011462	Young adult onset
HP:0012548	Fatty replacement of skeletal muscle
HP:0030951	Skeletal muscle fibrosis
HP:0033383	Decreased compound muscle action potential amplitude
HP:0000252	Microcephaly

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST008151_115	Waist circumference	3.000000e-06
GCST008158_133	Body mass index	9.000000e-06
GCST008160_67	Waist circumference	3.000000e-06
GCST009959_4	Retinal detachment or retinal break	3.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0010698	retinal break

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
C536194	Ehlers-Danlos syndrome type 1 (supp.)
C536195	Ehlers-Danlos syndrome type 2 (supp.)
C564181	Holoprosencephaly 3 (supp.)
C566370	Muscular Dystrophy, Limb-Girdle, Type 1D (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295674 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	affects cotreatment, increases expression, decreases expression	4
Tobacco Smoke Pollution	increases expression	3
Valproic Acid	affects expression, increases expression	3
sodium arsenite	decreases expression, increases abundance, increases expression	2
cobaltous chloride	increases expression	2
entinostat	increases expression, affects cotreatment	2
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation	2
Cadmium	increases expression	2
Copper	affects binding, decreases expression, increases expression	2
Silver	increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
beta-lapachone	decreases expression, increases expression	1
nickel chloride	increases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
coumarin	increases phosphorylation	1
cupric oxide	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
motexafin gadolinium	increases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
candoxin	increases expression	1
darinaparsin	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118642	Binding	Binding affinity to DNAJB6 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A2TF	GM27890	Transformed cell line	Female
CVCL_C7LZ	GM28910	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00455143	PHASE4	TERMINATED	Cognitive Protection - Dexmedetomidine and Cognitive Reserve
NCT00561678	PHASE4	COMPLETED	Perioperative Cognitive Function - Dexmedetomidine and Cognitive Reserve
NCT01807481	PHASE4	UNKNOWN	Phase IV Study to Evaluate the Efficacy and Safety of Mircera in PD
NCT07015671	PHASE3	COMPLETED	Bioavailability and Bioequivalence Study of ER Torsemide and Spironolactone FDC Tablet in Healthy Subjects
NCT03942458	PHASE1	COMPLETED	Pharmacokinetics and Pharmacodynamics of Vicagrel in Healthy Adult Subjects of Different CYP2C19
NCT07195825	PHASE1	RECRUITING	A Clinical Study to Evaluate the Safety, and Tolerability of BBM-P002 in the Treatment of Parkinson’s Disease
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT04093349	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Gene Transfer Study for Late-Onset Pompe Disease (RESOLUTE)
NCT07282847	PHASE1/PHASE2	RECRUITING	A Study to Evaluate Safety, Tolerability, and Efficacy of AB-1009 Gene Therapy (GAA Gene) in Adult Participants With Late Onset Pompe Disease (PROGRESS-GT LOPD)
NCT00105131	Not specified	COMPLETED	Genetic Characterization of Parkinson’s Disease
NCT03021408	Not specified	UNKNOWN	Effectiveness of Different Approaches for the Rehabilitation of Gait in Patients With Parkinson’s Disease
NCT03893240	Not specified	COMPLETED	Neutralizing Antibody Seroprevalence Study With a Retrospective Component in Participants With Late-Onset Pompe Disease
NCT05810454	Not specified	NOT_YET_RECRUITING	iPACES v3 MCI NIA Protocol Copied for iPACES v4 PD NINDS