DNAJC5

Summary

DNAJC5 (DnaJ heat shock protein family (Hsp40) member C5, HGNC:16235) is a protein-coding gene on chromosome 20q13.33, encoding DnaJ homolog subfamily C member 5 (Q9H3Z4). Acts as a general chaperone in regulated exocytosis.

This gene is a member of the J protein family. J proteins function in many cellular processes by regulating the ATPase activity of 70 kDa heat shock proteins. The encoded protein plays a role in membrane trafficking and protein folding, and has been shown to have anti-neurodegenerative properties. The encoded protein is known to play a role in cystic fibrosis and Huntington’s disease. A pseudogene of this gene is located on the short arm of chromosome 8.

Source: NCBI Gene 80331 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ceroid lipofuscinosis, neuronal, 4 (Kufs type) (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 5
• Clinical variants (ClinVar): 422 total — 4 pathogenic
• Phenotypes (HPO): 20
• Druggable target: yes
• MANE Select transcript: NM_025219

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16235
Approved symbol	DNAJC5
Name	DnaJ heat shock protein family (Hsp40) member C5
Location	20q13.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ00118, FLJ13070, DNAJC5A
Ensembl gene	ENSG00000101152
Ensembl biotype	protein_coding
OMIM	611203
Entrez	80331

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 9 protein_coding, 2 nonsense_mediated_decay

ENST00000360864, ENST00000470551, ENST00000703637, ENST00000898575, ENST00000898576, ENST00000898577, ENST00000921989, ENST00000921990, ENST00000961697, ENST00000961698, ENST00000961699

RefSeq mRNA: 1 — MANE Select: NM_025219 NM_025219

CCDS: CCDS13546

Canonical transcript exons

ENST00000360864 — 5 exons

Exon	Start	End
ENSE00000663600	63929312	63929525
ENSE00000663601	63930851	63931022
ENSE00002190190	63928335	63928452
ENSE00003514881	63931465	63936011
ENSE00003842128	63895126	63895323

Expression profiles

Bgee: expression breadth ubiquitous, 254 present calls, max score 96.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 54.0250 / max 442.2860, expressed in 1819 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185889	54.0250	1819

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cardiac muscle of right atrium	UBERON:0003379	96.17	silver quality
right frontal lobe	UBERON:0002810	95.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.45	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.26	gold quality
lower esophagus mucosa	UBERON:0035834	95.25	gold quality
cerebellar hemisphere	UBERON:0002245	95.07	gold quality
cerebellar cortex	UBERON:0002129	94.92	gold quality
pons	UBERON:0000988	94.91	gold quality
nucleus accumbens	UBERON:0001882	94.88	gold quality
left ventricle myocardium	UBERON:0006566	94.82	silver quality
gingival epithelium	UBERON:0001949	94.57	gold quality
nasal cavity epithelium	UBERON:0005384	94.57	silver quality
hypothalamus	UBERON:0001898	94.36	gold quality
esophagus squamous epithelium	UBERON:0006920	94.31	gold quality
prefrontal cortex	UBERON:0000451	94.30	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.10	gold quality
amygdala	UBERON:0001876	94.04	gold quality
cerebellum	UBERON:0002037	93.93	gold quality
putamen	UBERON:0001874	93.91	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.82	gold quality
substantia nigra pars compacta	UBERON:0001965	93.66	gold quality
esophagus mucosa	UBERON:0002469	93.63	gold quality
middle temporal gyrus	UBERON:0002771	93.63	gold quality
cortical plate	UBERON:0005343	93.32	gold quality
caudate nucleus	UBERON:0001873	93.13	gold quality
gingiva	UBERON:0001828	93.08	gold quality
upper arm skin	UBERON:0004263	93.02	silver quality
frontal cortex	UBERON:0001870	92.88	gold quality
granulocyte	CL:0000094	92.85	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF6

miRNA regulators (miRDB)

95 targeting DNAJC5, 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-5193	100.00	67.26	1744
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-1283	99.69	72.42	3009

Literature-anchored findings (GeneRIF, showing 32)

• Has a role in exocytosis of large dense core vesicles. (PMID:10194413)
• Csp has a role in regulated CFTR trafficking at the plasma membrane. [CYSTEINE STRING PROTEIN] (PMID:12039948)
• Cysteine string protein inhibits N-type calcium channels, but is blocked by mutant huntingtin (PMID:14570907)
• CSP modulates G protein function by preferentially targeting the inactive GDP-bound form of G alpha(s) and promoting GDP/GTP exchange; the guanine nucleotide exchange activity of full-length CSP is regulated by Hsc70-SGT (PMID:15972823)
• Cysteine string protein monitors late steps in cystic fibrosis transmembrane conductance regulator biogenesis (PMID:16469739)
• First evidence that CSP and HSP70, and their interactions with MARCKS, are involved in mucin secretion from airway epithelium. (PMID:18314541)
• palmitoylation of CSP is enhanced specifically by co-expression of the Golgi-localized palmitoyl transferases DHHC3, DHHC7, DHHC15, or DHHC17 (PMID:18596047)
• Csp not only regulates the exit of CFTR from the ER, but this action is accompanied by Hsc70/Hsp70 and CHIP-mediated CFTR degradation. (PMID:19098309)
• A neuroprotective role for CSPalpha in humans is confirmed. (PMID:21820099)
• This is the first replication study of the identification of DNAJC5 as the disease-causing gene for autosomal dominant ANCL. The identification of the novel gene in ANCL will allow us to gain a better understanding of the pathological mechanism of ANCLs (PMID:22073189)
• association of DNAJC5 mutations with autosomal dominant Kufs disease (PMID:22235333)
• Palmitoylation-induced aggregation of mutant CSP-alpha proteins may underlie the development of adult-onset neuronal ceroid lipofuscinosis (PMID:22902780)
• Results indicate of a p.L116del mutation in DNAJC5 from families with autosomal dominant Kufs disease. (PMID:22978711)
• Missense mutations in DNAJC5 does not play a major role in PD in the Chinese population. (PMID:24126164)
• the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer’s disease. (PMID:25631211)
• These results suggest that the degeneration seen in the patients with AD-ANCL reported here might be a consequence of both the early effects of CSPalpha mutations at the cellular soma. (PMID:26610600)
• This study demonstrated that Neuronal ceroid lipofuscinosis with DNAJC5/CSPalpha mutation has PPT1 pathology and exhibit aberrant protein palmitoylation. (PMID:26659577)
• In fact, DnaJC5 overexpression induced tau release in cells, neurons, and brain tissue, but only when activity of the chaperone Hsc70 was intact and when tau was able to associate with this chaperone. (PMID:27261198)
• Phosphorylation of CSP triggers a major conformational switch that modulates its protein interactions. (PMID:27452402)
• The importance of specific residues in the cysteine-string domain was investigated, revealing that a central core of palmitoylated cysteines is essential for aggregation of adult-onset neuronal ceroid lipofuscinosis CSPalpha L115R/L116 mutants. (PMID:28127059)
• Results indicate that by assisting local lysosome/proteasome processes, CSPalpha-mediated removal of toxic proteins via extracellular vesicles plays a central role in synaptic proteostasis. (PMID:28424476)
• Study demonstrate that primary dermal fibroblasts from asymptomatic mutation carriers recapitulate features of adult-neuronal ceroid lipofuscinosis (AD-ANCL) in vitro including CSPalpha-p.L115R/CSPalpha-WT aggregates and the structural and functional lysosomal dysfunction found in the brains of AD-ANCL patients. Further findings support a gain-of-function mechanism for CSPalpha mutations leading to AD-ANCL. (PMID:28740222)
• This report describes the clinical history of autosomal dominant Kufs disease, the genetic mutation within the DNAJC5 gene, and the neuropathological findings demonstrating depletion of choline acetyltransferase in the brain. (PMID:29506599)
• Clinical distinction of type A (progressive myoclonus epilepsy) and type B (dementia with motor disturbance) Kufs disease was supported by molecular diagnoses. Type A is usually caused by recessive pathogenic variants in CLN6 or dominant variants in DNAJC5. Type B Kufs is usually associated with recessive CTSF pathogenic variants. (PMID:30561534)
• Autosomal-dominant adult neuronal ceroid lipofuscinosis caused by duplication in DNAJC5 initially missed by Sanger and whole-exome sequencing. (PMID:31919451)
• Point mutations in cysteine string protein-alpha (CSP alpha) cause dominantly inherited adult-onset neuronal ceroid lipofuscinosis (ANCL). Normally palmitoylated cysteine string region of cysteine string protein alpha loses palmitoylation in ANCL mutants. (PMID:32042150)
• Autosomal dominant neuronal ceroid lipofuscinosis: Clinical features and molecular basis. (PMID:32783189)
• DNAJC5 promotes hepatocellular carcinoma cells proliferation though regulating SKP2 mediated p27 degradation. (PMID:33662413)
• Abnormal triaging of misfolded proteins by adult neuronal ceroid lipofuscinosis-associated DNAJC5/CSPalpha mutants causes lipofuscin accumulation. (PMID:35506243)
• The molecular chaperone cysteine string protein is required for monomeric SNARE proteins to assemble in trans-complexes during human sperm acrosomal exocytosisdagger. (PMID:36308432)
• Unconventional secretion of alpha-synuclein mediated by palmitoylated DNAJC5 oligomers. (PMID:36626307)
• LINC00624 affects hepatocellular carcinoma proliferation and apoptosis through the miR-342-3p/DNAJC5 axis. (PMID:38348704)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	dnajc5ab	ENSDARG00000004836
danio_rerio	dnajc5aa	ENSDARG00000042948
mus_musculus	Dnajc5	ENSMUSG00000000826
rattus_norvegicus	Dnajc5	ENSRNOG00000015202
drosophila_melanogaster	CG10565	FBGN0037051
drosophila_melanogaster	P58IPK	FBGN0037718
drosophila_melanogaster	l(3)80Fg	FBGN0287183
caenorhabditis_elegans		WBGENE00001020
caenorhabditis_elegans		WBGENE00001025
caenorhabditis_elegans		WBGENE00001026
caenorhabditis_elegans		WBGENE00001029
caenorhabditis_elegans	dnj-28	WBGENE00001046
caenorhabditis_elegans		WBGENE00008122

Paralogs (20): DNAJC11 (ENSG00000007923), DNAJC25 (ENSG00000059769), DNAJC10 (ENSG00000077232), DNAJC3 (ENSG00000102580), DNAJC17 (ENSG00000104129), DNAJC2 (ENSG00000105821), DNAJC12 (ENSG00000108176), DNAJC4 (ENSG00000110011), DNAJC16 (ENSG00000116138), DNAJC14 (ENSG00000135392), DNAJC1 (ENSG00000136770), DNAJC13 (ENSG00000138246), DNAJC5B (ENSG00000147570), DNAJC5G (ENSG00000163793), DNAJC7 (ENSG00000168259), DNAJC21 (ENSG00000168724), DNAJC18 (ENSG00000170464), DNAJC24 (ENSG00000170946), DNAJC30 (ENSG00000176410), DNAJC9 (ENSG00000213551)

Protein

Protein identifiers

DnaJ homolog subfamily C member 5 — Q9H3Z4 (reviewed: Q9H3Z4)

Alternative names: Ceroid-lipofuscinosis neuronal protein 4, Cysteine string protein

All UniProt accessions (1): Q9H3Z4

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a general chaperone in regulated exocytosis. Acts as a co-chaperone for the SNARE protein SNAP-25. Involved in the calcium-mediated control of a late stage of exocytosis. May have an important role in presynaptic function. May be involved in calcium-dependent neurotransmitter release at nerve endings.

Subunit / interactions. Oligomers. Homodimer. Interacts with the chaperone complex consisting of HSC70 and SGTA. Interacts with ZDHHC13 (via ANK repeats). Interacts with ZDHHC17 (via ANK repeats). Interacts with SYT1, SYT5 and SYT7, and with SYT9, forming a complex with SNAP25.

Subcellular location. Cytoplasm. Cytosol. Membrane. Cytoplasmic vesicle. Secretory vesicle. Chromaffin granule membrane. Melanosome. Cell membrane.

Tissue specificity. Expressed in pancreas, kidney, skeletal muscle, liver, lung, placenta, brain and heart.

Post-translational modifications. Ser-10 phosphorylation induces an order-to-disorder transition triggering the interaction with Lys-58. This conformational switch modulates DNAJC5’s cellular functions by reducing binding to syntaxin and synaptogamin without altering HSC70 interactions. Palmitoylated. Could be palmitoylated by DHHC3, DHHC7, DHHC15 and DHHC17. Palmitoylation occurs probably in the cysteine-rich domain and regulates DNAJC5 membrane attachment.

Disease relevance. Ceroid lipofuscinosis, neuronal, 4B (Kufs type), autosomal dominant (CLN4B) [MIM:162350] An adult-onset neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. CLN4B has no visual involvement and is characterized by seizures and other neurologic symptoms. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Upon phosphorylation, Ser-10 interacts with Lys-58, a highly conserved residue in DnaJ proteins that is also a ubiquitination site in DNAJC5.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H3Z4-1	1	yes
Q9H3Z4-2	2

RefSeq proteins (1): NP_079495* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001623	DnaJ_domain	Domain
IPR018253	DnaJ_domain_CS	Conserved_site
IPR036869	J_dom_sf	Homologous_superfamily
IPR051434	DnaJ_C_subfamily_member5	Family

Pfam: PF00226

UniProt features (25 total): helix 7, modified residue 7, turn 3, sequence variant 2, mutagenesis site 2, chain 1, domain 1, strand 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2N04	SOLUTION NMR
2N05	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H3Z4-F1	74.09	0.24

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 (7): 8, 10, 12, 15, 17, 56, 151

Mutagenesis-validated functional residues (2):

Position	Phenotype
10	increased syntaxin binding.
113–136	no effect on oligomerization.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation
R-HSA-888590	GABA synthesis, release, reuptake and degradation
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea

MSigDB gene sets: 172 (showing top): GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_PROTEIN_MATURATION, GROSS_HYPOXIA_VIA_HIF1A_DN, GOCC_COATED_VESICLE, ACATTCC_MIR1_MIR206, GOBP_SECRETION, GOBP_SIGNAL_RELEASE

GO Biological Process (7): protein folding (GO:0006457), exocytosis (GO:0006887), synaptic vesicle exocytosis (GO:0016079), negative regulation of neuron apoptotic process (GO:0043524), regulated exocytosis (GO:0045055), neuron apoptotic process (GO:0051402), regulation of synaptic vesicle cycle (GO:0098693)

GO Molecular Function (2): ATP-dependent protein binding (GO:0043008), protein binding (GO:0005515)

GO Cellular Component (16): mitochondrion (GO:0005739), lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), synaptic vesicle membrane (GO:0030672), neuromuscular junction (GO:0031594), azurophil granule membrane (GO:0035577), specific granule membrane (GO:0035579), melanosome (GO:0042470), chromaffin granule membrane (GO:0042584), clathrin-sculpted gamma-aminobutyric acid transport vesicle membrane (GO:0061202), presynapse (GO:0098793), cytoplasm (GO:0005737), synaptic vesicle (GO:0008021), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Innate Immune System	1
Neurotransmitter release cycle	1
Sensory processing of sound	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cytoplasm	3
secretory granule membrane	3
presynapse	2
synaptic vesicle cycle	2
synapse	2
cellular process	1
protein maturation	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
vesicle-mediated transport in synapse	1
signal release from synapse	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
exocytosis	1
apoptotic process	1
regulation of vesicle-mediated transport	1
protein binding	1
binding	1
intracellular membrane-bounded organelle	1
lysosome	1
lytic vacuole membrane	1
membrane	1
cell periphery	1
synaptic vesicle	1
exocytic vesicle membrane	1
lysosomal membrane	1
azurophil granule	1
specific granule	1
pigment granule	1
chromaffin granule	1
clathrin-coated vesicle membrane	1
clathrin-sculpted gamma-aminobutyric acid transport vesicle	1
intracellular anatomical structure	1
exocytic vesicle	1

Protein interactions and networks

STRING

3283 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DNAJC5	HSPA8	P11142	984
DNAJC5	PPT1	P50897	915
DNAJC5	CLN3	Q13286	911
DNAJC5	CLN6	Q9NWW5	862
DNAJC5	CLN8	Q9UBY8	847
DNAJC5	MFSD8	Q8NHS3	838
DNAJC5	CLN5	O75503	837
DNAJC5	SGTA	O43765	819
DNAJC5	SYT1	P21579	779
DNAJC5	TPP1	O14773	778
DNAJC5	VAMP2	P19065	747
DNAJC5	KCTD7	Q96MP8	713
DNAJC5	HSPA4	P34932	696
DNAJC5	ZDHHC17	Q8IUH5	690
DNAJC5	CTSD	P07339	682

IntAct

94 interactions, top by confidence:

A	B	Type	Score
DNAJC5	ZDHHC17	psi-mi:“MI:0403”(colocalization)	0.640
DNAJC5	ZDHHC17	psi-mi:“MI:2364”(proximity)	0.640
DNAJC5	ZDHHC17	psi-mi:“MI:0915”(physical association)	0.640
NECTIN2	DNAJC5	psi-mi:“MI:2364”(proximity)	0.470
SLC6A1	DNAJC5	psi-mi:“MI:2364”(proximity)	0.470
NECTIN2	DNAJC5	psi-mi:“MI:0915”(physical association)	0.470
SLC6A1	DNAJC5	psi-mi:“MI:0915”(physical association)	0.470
DNAJC5	AP2A1	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	AP2S1	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	SLC17A7	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	SLC17A8	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	SLC18A3	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	SLC32A1	psi-mi:“MI:0915”(physical association)	0.400
BEST1	DNAJC5	psi-mi:“MI:0915”(physical association)	0.400
FANCC	DNAJC5	psi-mi:“MI:0915”(physical association)	0.400
L3MBTL2	DNAJC5	psi-mi:“MI:0915”(physical association)	0.400
PSTPIP2	DNAJC5	psi-mi:“MI:0915”(physical association)	0.400
SKP2	DNAJC5	psi-mi:“MI:0915”(physical association)	0.400
TRAF6	DNAJC5	psi-mi:“MI:0915”(physical association)	0.400
ATP6V1A		psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
Npc1	ESYT2	psi-mi:“MI:0914”(association)	0.350
DNAJC5	DNAJA2	psi-mi:“MI:0914”(association)	0.350
DNAJC5	HIDE1	psi-mi:“MI:0914”(association)	0.350
PLAAT1	HIDE1	psi-mi:“MI:0914”(association)	0.350
PTGFR	ATP12A	psi-mi:“MI:0914”(association)	0.350

BioGRID (425): DNAJC5 (Affinity Capture-MS), DNAJC5 (Affinity Capture-Western), DNAJC5 (Affinity Capture-MS), DNAJC5 (Affinity Capture-RNA), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET), DNAJC5 (FRET)

ESM2 similar proteins: A6NKW6, A6QQ93, D2H417, D3ZD82, F1RTY8, H2KZH5, O14213, O42196, O59731, P13895, P19836, P27426, P36707, P49584, P49585, P49586, P55082, P56101, P60904, P60905, Q03751, Q06651, Q10209, Q11100, Q17438, Q28I38, Q29455, Q2KIJ8, Q2QUP1, Q552Z6, Q5EA26, Q5R6H3, Q5R9E4, Q6AYF7, Q6FQ33, Q6FS52, Q7ZXQ8, Q86ME2, Q8GYX8, Q8N7S2

Diamond homologs: A1V9Q3, A3N3J9, A4G8D1, A4XYF5, A5N6M3, A5W9A2, A6Q486, A6QBG7, A6T225, A6VCL7, A9IGC5, B0BTI6, B0KIS4, B1J255, B2TLZ8, B2UBP2, B2V2I6, B7V1H2, B9FHF3, C1DD87, C1DFM2, C3K274, D2H417, D3ZD82, F1RTY8, O42196, O54946, O75190, O89114, P0CW06, P0CW07, P30725, P43735, P50027, P56101, P60904, P60905, P81999, Q02FR2, Q03751

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKACA	unknown	DNAJC5	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 86 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
Dopamine Neurotransmitter Release Cycle	7	50.4×	6e-09
Acetylcholine Neurotransmitter Release Cycle	5	48.7×	3e-06
Neurotransmitter release cycle	6	38.2×	8e-07
Glutamate Neurotransmitter Release Cycle	5	33.1×	2e-05
Cargo recognition for clathrin-mediated endocytosis	16	24.3×	7e-16
Clathrin-mediated endocytosis	16	19.8×	1e-14
Protein-protein interactions at synapses	5	19.2×	2e-04
Recycling pathway of L1	5	16.2×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
vesicle fusion	8	60.2×	3e-10
obsolete vesicle docking	5	47.9×	7e-06
neurotransmitter secretion	5	43.9×	9e-06
clathrin-dependent endocytosis	5	36.3×	2e-05
synaptic vesicle endocytosis	5	27.0×	9e-05
synapse organization	5	17.6×	4e-04
exocytosis	9	17.1×	6e-07
vesicle-mediated transport	8	9.6×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	0
Uncertain significance	185
Likely benign	136
Benign	54

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
1178346	NM_025219.3(DNAJC5):c.347T>G (p.Leu116Arg)	Pathogenic
30893	NM_025219.3(DNAJC5):c.343CTC[1] (p.Leu116del)	Pathogenic
30894	NM_025219.3(DNAJC5):c.344T>G (p.Leu115Arg)	Pathogenic
689476	NM_025219.3(DNAJC5):c.370_399dup (p.Cys124_Cys133dup)	Pathogenic

SpliceAI

1220 predictions. Top by Δscore:

Variant	Effect	Δscore
20:63928331:CTA:C	acceptor_loss	1.0000
20:63928333:A:AG	acceptor_gain	1.0000
20:63928333:A:AT	acceptor_loss	1.0000
20:63928334:G:GA	acceptor_gain	1.0000
20:63928334:GA:G	acceptor_gain	1.0000
20:63928334:GAA:G	acceptor_gain	1.0000
20:63928334:GAAT:G	acceptor_gain	1.0000
20:63928334:GAATA:G	acceptor_gain	1.0000
20:63928451:CGG:C	donor_loss	1.0000
20:63928453:G:GG	donor_gain	1.0000
20:63928453:GT:G	donor_loss	1.0000
20:63928454:TAAGT:T	donor_loss	1.0000
20:63929306:TTGCA:T	acceptor_loss	1.0000
20:63929308:GCA:G	acceptor_loss	1.0000
20:63929310:A:AG	acceptor_gain	1.0000
20:63929310:AG:A	acceptor_gain	1.0000
20:63929311:G:GG	acceptor_gain	1.0000
20:63929311:GG:G	acceptor_gain	1.0000
20:63929311:GGA:G	acceptor_gain	1.0000
20:63929311:GGAA:G	acceptor_gain	1.0000
20:63929478:G:T	donor_gain	1.0000
20:63930847:CCA:C	acceptor_loss	1.0000
20:63930848:CAGG:C	acceptor_loss	1.0000
20:63930849:A:AG	acceptor_gain	1.0000
20:63930849:AG:A	acceptor_gain	1.0000
20:63930849:AGGC:A	acceptor_loss	1.0000
20:63930850:G:A	acceptor_loss	1.0000
20:63930850:G:GA	acceptor_gain	1.0000
20:63930850:GG:G	acceptor_gain	1.0000
20:63930850:GGC:G	acceptor_gain	1.0000

AlphaMissense

1305 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:63928382:G:T	G13W	1.000
20:63928404:T:A	L20H	1.000
20:63928404:T:C	L20P	1.000
20:63928448:T:C	Y35H	1.000
20:63928448:T:G	Y35D	1.000
20:63928452:G:C	R36P	1.000
20:63929317:T:C	L38P	1.000
20:63929319:G:A	A39T	1.000
20:63929320:C:A	A39D	1.000
20:63929323:T:C	L40S	1.000
20:63929323:T:G	L40W	1.000
20:63929331:C:A	H43N	1.000
20:63929331:C:G	H43D	1.000
20:63929331:C:T	H43Y	1.000
20:63929332:A:G	H43R	1.000
20:63929333:C:A	H43Q	1.000
20:63929333:C:G	H43Q	1.000
20:63929334:C:A	P44T	1.000
20:63929334:C:T	P44S	1.000
20:63929335:C:A	P44H	1.000
20:63929337:G:A	D45N	1.000
20:63929337:G:C	D45H	1.000
20:63929338:A:C	D45A	1.000
20:63929338:A:G	D45G	1.000
20:63929338:A:T	D45V	1.000
20:63929340:A:G	K46E	1.000
20:63929341:A:T	K46M	1.000
20:63929342:G:C	K46N	1.000
20:63929342:G:T	K46N	1.000
20:63929373:T:C	F57L	1.000

dbSNP variants (sampled 300 via entrez): RS1000182428 (20:63907840 A>G), RS1000195295 (20:63902810 G>A,C), RS1000279485 (20:63934543 C>T), RS1000348832 (20:63921220 A>G), RS1000431326 (20:63897675 C>A,G,T), RS1000532542 (20:63901215 T>G), RS1000548272 (20:63906756 A>C), RS1000566810 (20:63909503 A>G), RS1000618040 (20:63908057 C>T), RS1000647004 (20:63901391 C>G,T), RS1000799952 (20:63929047 G>A), RS1000832328 (20:63916099 A>C), RS1000922708 (20:63906632 A>G), RS1000987101 (20:63929904 G>A), RS1001004530 (20:63911296 G>A)

Disease associations

OMIM: gene MIM:611203 | disease phenotypes: MIM:256730, MIM:162350, MIM:600513

GenCC curated gene-disease

Disease	Classification	Inheritance
ceroid lipofuscinosis, neuronal, 4 (Kufs type)	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
adult neuronal ceroid lipofuscinosis	Moderate	AD

Mondo (3): neuronal ceroid lipofuscinosis (MONDO:0016295), ceroid lipofuscinosis, neuronal, 4 (Kufs type) (MONDO:0008083), familial sleep-related hypermotor epilepsy (MONDO:0000030)

Orphanet (5): Neuronal ceroid lipofuscinosis (Orphanet:216), OBSOLETE: Infantile neuronal ceroid lipofuscinosis (Orphanet:79263), CLN4 disease (Orphanet:228343), OBSOLETE: Adult neuronal ceroid lipofuscinosis (Orphanet:79262), Sleep-related hypermotor epilepsy (Orphanet:98784)

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000716	Depression
HP:0000726	Dementia
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001300	Parkinsonism
HP:0001317	Abnormal cerebellum morphology
HP:0001336	Myoclonus
HP:0002069	Bilateral tonic-clonic seizure
HP:0002071	Abnormality of extrapyramidal motor function
HP:0002074	Increased neuronal autofluorescent lipopigment
HP:0002367	Visual hallucination
HP:0003205	Curvilinear intracellular accumulation of autofluorescent lipopigment storage material
HP:0003208	Fingerprint intracellular accumulation of autofluorescent lipopigment storage material
HP:0003226	Rectilinear intracellular accumulation of autofluorescent lipopigment storage material
HP:0003657	Vascular granular osmiophilic material deposition
HP:0003678	Rapidly progressive
HP:0008765	Auditory hallucination
HP:0011462	Young adult onset
HP:0032794	Myoclonic seizure

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST001942_22	Prostate cancer	4.000000e-16
GCST90002387_171	Immature fraction of reticulocytes	3.000000e-11
GCST90002395_610	Mean platelet volume	5.000000e-15
GCST90002396_71	Mean reticulocyte volume	6.000000e-29
GCST90002397_293	Mean spheric corpuscular volume	1.000000e-13

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010701	mean reticulocyte volume

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C579932	Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067410 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases mutagenesis, affects methylation, decreases methylation	3
Tobacco Smoke Pollution	affects expression, increases expression	3
bisphenol A	decreases methylation, decreases expression, affects cotreatment	2
Estradiol	affects expression, increases expression	2
FR900359	affects phosphorylation	1
lasiocarpine	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects localization, increases expression, affects cotreatment	1
sodium arsenite	affects expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
cupric oxide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Air Pollutants	affects expression, increases abundance	1
Arsenic	affects methylation	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Diclofenac	affects expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Furaldehyde	affects cotreatment, affects localization, decreases expression, increases expression	1
Gold	affects binding, decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651295	Binding	Binding affinity to human DNAJC5 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 1 transformed cell line, 1 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_C8UP	HEK293T DNAJC5 KO	Transformed cell line	Female
CVCL_C8UQ	SH-SY5Y DNAJC5 KD	Cancer cell line	Female
CVCL_F0PT	H9 AAVS1-TRE3G-NGN2 TMEM192-3xHA (heterozygous) DNAJC5-/-	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00337636	PHASE1	COMPLETED	Study of HuCNS-SC Cells in Patients With Infantile or Late Infantile Neuronal Ceroid Lipofuscinosis (NCL)
NCT01238315	PHASE1	WITHDRAWN	Safety and Efficacy Study of HuCNS-SC in Subjects With Neuronal Ceroid Lipofuscinosis
NCT07582484	PHASE1/PHASE2	NOT_YET_RECRUITING	Gene Therapy Trial for CLN6 Batten Disease
NCT01873924	Not specified	RECRUITING	Clinical and Neuropsychological Investigations in Batten Disease
NCT01966757	Not specified	COMPLETED	Neuronal Ceroid Lipofuscinosis and Associated Sleep Abnormalities
NCT04613089	Not specified	RECRUITING	Natural History and Longitudinal Clinical Assessments in NCL / Batten Disease, the International DEM-CHILD Database
NCT06844877	Not specified	RECRUITING	Italian NCL Registry: a Registry for NCL as an Integration Tool for Future Therapeutic Strategies