HPCA

Summary

HPCA (hippocalcin, HGNC:5144) is a protein-coding gene on chromosome 1p35.1, encoding Neuron-specific calcium-binding protein hippocalcin (P84074). Calcium-binding protein that may play a role in the regulation of voltage-dependent calcium channels.

The protein encoded by this gene is a member of neuron-specific calcium-binding proteins family found in the retina and brain. This protein is associated with the plasma membrane. It has similarities to proteins located in the photoreceptor cells that regulate photosignal transduction in a calcium-sensitive manner. This protein displays recoverin activity and a calcium-dependent inhibition of rhodopsin kinase. It is identical to the rat and mouse hippocalcin proteins and thought to play an important role in neurons of the central nervous system in a number of species.

Source: NCBI Gene 3208 — RefSeq curated summary.

At a glance

• Gene–disease (curated): complex movement disorder with or without neurodevelopmental features (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 66 total — 3 pathogenic
• MANE Select transcript: NM_002143

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5144
Approved symbol	HPCA
Name	hippocalcin
Location	1p35.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000121905
Ensembl biotype	protein_coding
OMIM	142622
Entrez	3208

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000373467, ENST00000459874, ENST00000470166, ENST00000470896, ENST00000480118, ENST00000854771, ENST00000854772, ENST00000854773, ENST00000854774, ENST00000947034, ENST00000947035

RefSeq mRNA: 1 — MANE Select: NM_002143 NM_002143

CCDS: CCDS370

Canonical transcript exons

ENST00000373467 — 4 exons

Exon	Start	End
ENSE00001460634	32893765	32894646
ENSE00001896875	32886491	32886515
ENSE00003495827	32893524	32893629
ENSE00003569223	32888878	32889276

Expression profiles

Bgee: expression breadth ubiquitous, 189 present calls, max score 99.55.

FANTOM5 (CAGE): breadth broad, TPM avg 16.5689 / max 2549.1672, expressed in 206 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2032	13.6794	130
2031	1.4058	91
2030	0.7399	87
2028	0.3211	81
2035	0.1618	97
2036	0.1376	48
2034	0.0698	33
2029	0.0535	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
caudate nucleus	UBERON:0001873	99.55	gold quality
middle frontal gyrus	UBERON:0002702	99.47	gold quality
putamen	UBERON:0001874	99.44	gold quality
nucleus accumbens	UBERON:0001882	98.99	gold quality
lateral globus pallidus	UBERON:0002476	98.62	gold quality
prefrontal cortex	UBERON:0000451	98.23	gold quality
right frontal lobe	UBERON:0002810	98.08	gold quality
CA1 field of hippocampus	UBERON:0003881	97.96	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.86	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.35	gold quality
Ammon’s horn	UBERON:0001954	97.33	gold quality
cingulate cortex	UBERON:0003027	97.20	gold quality
anterior cingulate cortex	UBERON:0009835	97.16	gold quality
frontal cortex	UBERON:0001870	96.86	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.85	gold quality
frontal pole	UBERON:0002795	96.45	gold quality
telencephalon	UBERON:0001893	96.39	gold quality
neocortex	UBERON:0001950	96.17	gold quality
cerebral cortex	UBERON:0000956	96.05	gold quality
amygdala	UBERON:0001876	96.04	gold quality
Brodmann (1909) area 46	UBERON:0006483	95.53	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.33	gold quality
postcentral gyrus	UBERON:0002581	94.92	gold quality
temporal lobe	UBERON:0001871	94.87	gold quality
cerebellar hemisphere	UBERON:0002245	94.72	gold quality
cerebellar cortex	UBERON:0002129	94.53	gold quality
entorhinal cortex	UBERON:0002728	94.45	gold quality
superior frontal gyrus	UBERON:0002661	94.38	gold quality
orbitofrontal cortex	UBERON:0004167	94.30	gold quality
parietal lobe	UBERON:0001872	94.29	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	5223.09
E-MTAB-7316	yes	1288.57
E-ANND-3	no	1.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

50 targeting HPCA, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-3133	99.81	70.92	3506
HSA-MIR-6745	99.74	65.33	1321
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-363-5P	99.46	64.51	1015
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-488-5P	99.28	68.12	821
HSA-MIR-6803-5P	99.19	63.90	1026

Literature-anchored findings (GeneRIF, showing 12)

• Hippocalcin is a sensitive Ca2+ sensor capable of responding to increases in intracellular Ca2+ concentration over the narrow dynamic range of 200-800 nM free Ca2+. (PMID:14638856)
• The structural factors affecting the binding of hippocalcin to phosphatidylinositol 4,5-bisphosphate at the cell surface and the Golgi apparatus are described. (PMID:16053445)
• Hippocalcin and MLK2 were colocalized in the halo of Lewy bodies in Parkinson disease patients, and neither protein was detected in normal pigmented neurons. (PMID:19332348)
• diminished hippocalcin expression does not contribute to Huntington disease-related neurodegeneration (PMID:19686238)
• analysis of a novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents (PMID:22544757)
• Current known dystonia genes include those related to dopamine metabolism, transcription factor, cytoskeleton, transport of glucose and sodium ion, etc. (PMID:23782819)
• Mutations in HPCA cause autosomal-recessive primary isolated dystonia. (PMID:25799108)
• Sequence analysis of the HPCA gene in 505 patients with dystonia did not reveal variants in the coding regions of HPCA. (PMID:27145302)
• None of the patients enrolled was found to carry HPCA mutations, rising suspicion that these probably represent a very rare cause of dystonia in childhood-adolescence. (PMID:27771228)
• hippocalcin forms oligomers upon calcium binding and directly interacts with VGCCs. The dystonia-causing mutations did not affect protein stability or folding. In common for both T71N and A190T mutants was an impaired calcium-dependent oligomerisation and increased intracellular calcium influx after KCl depolarisation. (PMID:28398555)
• HPCA mutations lead to recessively inherited dystonia (PMID:30145809)
• MiR-24-3p is an important miRNA that regulates neuronal differentiation by controlling HPCA expression. (PMID:31486848)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hpca	ENSDARG00000018397
mus_musculus	Hpca	ENSMUSG00000028785
rattus_norvegicus	Hpca	ENSRNOG00000006979
drosophila_melanogaster	CG7646	FBGN0036926
caenorhabditis_elegans	ncs-2	WBGENE00003564

Paralogs (14): CLXN (ENSG00000034239), GUCA1A (ENSG00000048545), NCALD (ENSG00000104490), NCS1 (ENSG00000107130), RCVRN (ENSG00000109047), GUCA1B (ENSG00000112599), KCNIP3 (ENSG00000115041), HPCAL1 (ENSG00000115756), HPCAL4 (ENSG00000116983), KCNIP2 (ENSG00000120049), GUCA1C (ENSG00000138472), VSNL1 (ENSG00000163032), KCNIP1 (ENSG00000182132), KCNIP4 (ENSG00000185774)

Protein

Protein identifiers

Neuron-specific calcium-binding protein hippocalcin — P84074 (reviewed: P84074)

Alternative names: Calcium-binding protein BDR-2

All UniProt accessions (1): P84074

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-binding protein that may play a role in the regulation of voltage-dependent calcium channels. May also play a role in cyclic-nucleotide-mediated signaling through the regulation of adenylate and guanylate cyclases.

Subunit / interactions. Oligomer; oligomerization is calcium-dependent. May interact with the voltage-dependent P/Q- and N-type calcium channels CACNA1A and CACNA1B.

Subcellular location. Cytoplasm. Cytosol. Membrane.

Tissue specificity. Brain specific.

Post-translational modifications. Myristoylation facilitates association with membranes.

Disease relevance. Dystonia 2, torsion, autosomal recessive (DYT2) [MIM:224500] A form of torsion dystonia, a disease defined by the presence of sustained involuntary muscle contractions, often leading to abnormal postures. ‘Torsion’ refers to the twisting nature of body movements, often affecting the trunk. DYT2 is a slowly progressive form that first affects distal limbs and later involves the neck, orofacial, and craniocervical regions. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Binds 3 calcium via EF-hand domains. The cryptic EF-hand 1 does not bind calcium.

Similarity. Belongs to the recoverin family.

RefSeq proteins (1): NP_002134* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR028846	Recoverin	Family

Pfam: PF00036, PF13499

UniProt features (46 total): binding site 15, helix 10, strand 6, domain 4, sequence variant 4, sequence conflict 2, turn 2, initiator methionine 1, chain 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7OWM	X-RAY DIFFRACTION	1.5
5G4P	X-RAY DIFFRACTION	2.42
5G58	X-RAY DIFFRACTION	2.54
5M6C	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P84074-F1	86.87	0.64

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (15): 84; 109; 111; 113; 115; 120; 157; 159; 161; 163; 168; 73 …

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 215 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, TGCGCANK_UNKNOWN, GOBP_RESPONSE_TO_ACID_CHEMICAL, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, MAZ_Q6, GOBP_PROTEIN_TARGETING, GOBP_REGULATION_OF_VOLTAGE_GATED_CALCIUM_CHANNEL_ACTIVITY, MODULE_264, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_PROTEIN_TARGETING_TO_MEMBRANE, GOBP_CELLULAR_RESPONSE_TO_ACID_CHEMICAL, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, USF_C

GO Biological Process (13): regulation of signal transduction (GO:0009966), calcium-mediated signaling (GO:0019722), inner ear development (GO:0048839), retina development in camera-type eye (GO:0060041), cellular response to electrical stimulus (GO:0071257), cellular response to calcium ion (GO:0071277), positive regulation of protein targeting to membrane (GO:0090314), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), regulation of voltage-gated calcium channel activity (GO:1901385), response to ketamine (GO:1901986), response to Aroclor 1254 (GO:1904010), cellular response to L-glutamate (GO:1905232), response to L-glutamate (GO:1902065)

GO Molecular Function (6): actin binding (GO:0003779), calcium ion binding (GO:0005509), kinase binding (GO:0019900), identical protein binding (GO:0042802), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (11): cytoplasm (GO:0005737), cytosol (GO:0005829), membrane (GO:0016020), axon (GO:0030424), dendrite membrane (GO:0032590), neuronal cell body membrane (GO:0032809), dendrite cytoplasm (GO:0032839), perikaryon (GO:0043204), dendritic spine head (GO:0044327), glutamatergic synapse (GO:0098978), postsynapse (GO:0098794)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
anatomical structure development	2
response to nitrogen compound	2
dendrite	2
neuronal cell body	2
synapse	2
signal transduction	1
regulation of cell communication	1
regulation of signaling	1
regulation of response to stimulus	1
intracellular signaling cassette	1
ear development	1
camera-type eye development	1
response to electrical stimulus	1
cellular response to abiotic stimulus	1
response to calcium ion	1
cellular response to metal ion	1
protein targeting to membrane	1
positive regulation of cellular process	1
regulation of protein targeting to membrane	1
positive regulation of establishment of protein localization	1
regulation of receptor internalization	1
regulation of biological quality	1
postsynaptic neurotransmitter receptor internalization	1
voltage-gated calcium channel activity	1
regulation of transmembrane transporter activity	1
response to ketone	1
response to chemical	1
cellular response to amino acid stimulus	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
response to L-glutamate	1
response to amino acid	1
response to oxygen-containing compound	1
cytoskeletal protein binding	1
metal ion binding	1
enzyme binding	1
protein binding	1
binding	1
cation binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

67 interactions, top by confidence:

A	B	Type	Score
HPCA	DTX2	psi-mi:“MI:0915”(physical association)	0.670
HPCA	CKMT1A	psi-mi:“MI:0915”(physical association)	0.560
HPCA	GATA5	psi-mi:“MI:0915”(physical association)	0.560
IL36RN	HPCA	psi-mi:“MI:0915”(physical association)	0.560
HPCA	MYDGF	psi-mi:“MI:0915”(physical association)	0.560
HPCA	CREM	psi-mi:“MI:0915”(physical association)	0.560
PRR35	HPCA	psi-mi:“MI:0915”(physical association)	0.560
HPCA	C1QTNF2	psi-mi:“MI:0915”(physical association)	0.560
HPCA	VWC2	psi-mi:“MI:0915”(physical association)	0.560
SLC16A3	HPCA	psi-mi:“MI:0915”(physical association)	0.560
HPCA	TEPSIN	psi-mi:“MI:0915”(physical association)	0.560
CKMT1A	HPCA	psi-mi:“MI:0915”(physical association)	0.560
MLLT10	HPCA	psi-mi:“MI:0915”(physical association)	0.560
HPCA	IL36RN	psi-mi:“MI:0915”(physical association)	0.560
UQCRB	HPCA	psi-mi:“MI:0915”(physical association)	0.560
NUFIP1	PDE2A	psi-mi:“MI:0914”(association)	0.530
NCALD	TPP2	psi-mi:“MI:0914”(association)	0.530
NUFIP1	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
HAX1	GPM6B	psi-mi:“MI:0914”(association)	0.350
DGUOK	DNM1L	psi-mi:“MI:0914”(association)	0.350
DNAAF2	DNM1L	psi-mi:“MI:0914”(association)	0.350
TEX101	PSMD12	psi-mi:“MI:0914”(association)	0.350
TEX101	NDUFA4	psi-mi:“MI:0914”(association)	0.350

BioGRID (58): HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Affinity Capture-MS), HPCA (Two-hybrid), HPCA (Two-hybrid), HPCA (Two-hybrid), HPCA (Two-hybrid), GATA5 (Two-hybrid), IL36RN (Two-hybrid), SLC16A3 (Two-hybrid)

ESM2 similar proteins: A9JTH1, B3DLU1, B3VSB7, B5FZ84, P29104, P29105, P35332, P36608, P37235, P37236, P42324, P42325, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762, P62763, P62764, P84074, P84075, P84076, Q06AT0, Q06AT1, Q09711, Q16982, Q28IM6, Q4PL64, Q4R4N4, Q4R5F7, Q5PQN0, Q5R632, Q5R6S5

Diamond homologs: A9JTH1, B3DLU1, B3VSB7, B5FZ84, O73761, O73762, O73763, O95843, P21457, P22728, P25296, P29104, P29105, P31227, P34057, P35243, P35332, P36608, P36609, P37235, P37236, P42322, P42324, P42325, P43080, P43081, P46065, P51177, P61601, P61602, P62166, P62167, P62168, P62748, P62749, P62758, P62759, P62760, P62761, P62762

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	28
Likely benign	32
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
190118	NM_002143.3(HPCA):c.225C>A (p.Asn75Lys)	Pathogenic
190119	NM_002143.3(HPCA):c.212C>A (p.Thr71Asn)	Pathogenic
3247938	NC_000001.10:g.(?33354500)(33359463_?)del	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1301 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:32888998:T:C	F34L	1.000
1:32889000:C:A	F34L	1.000
1:32889000:C:G	F34L	1.000
1:32889211:T:C	F105L	1.000
1:32889213:C:A	F105L	1.000
1:32889213:C:G	F105L	1.000
1:32888945:T:C	L16P	0.999
1:32888962:T:C	F22L	0.999
1:32888963:T:C	F22S	0.999
1:32888964:C:A	F22L	0.999
1:32888964:C:G	F22L	0.999
1:32888978:T:C	L27P	0.999
1:32888999:T:C	F34S	0.999
1:32889026:T:A	L43H	0.999
1:32889026:T:C	L43P	0.999
1:32889041:T:C	F48S	0.999
1:32889064:T:C	F56L	0.999
1:32889066:T:A	F56L	0.999
1:32889066:T:G	F56L	0.999
1:32889088:T:C	F64L	0.999
1:32889089:T:C	F64S	0.999
1:32889089:T:G	F64C	0.999
1:32889090:T:A	F64L	0.999
1:32889090:T:G	F64L	0.999
1:32889092:C:A	A65D	0.999
1:32889101:T:A	V68D	0.999
1:32889103:T:C	F69L	0.999
1:32889105:C:A	F69L	0.999
1:32889105:C:G	F69L	0.999
1:32889107:G:C	R70P	0.999

dbSNP variants (sampled 300 via entrez): RS1000531329 (1:32893441 G>A,C), RS1000758361 (1:32889003 C>G,T), RS1000810631 (1:32888441 C>T), RS1000853018 (1:32885549 A>G,T), RS1000960075 (1:32895089 C>G), RS1001365596 (1:32884882 C>T), RS1001418029 (1:32884643 G>A), RS1001438474 (1:32891649 CTG>C), RS1001477041 (1:32892015 G>A), RS1001653236 (1:32888374 G>A), RS1001814408 (1:32890333 T>G), RS1002515750 (1:32893120 C>T), RS1002723504 (1:32885095 T>C), RS1003241160 (1:32885452 C>T), RS1003330605 (1:32890123 G>A)

Disease associations

OMIM: gene MIM:142622 | disease phenotypes: MIM:224500

GenCC curated gene-disease

Disease	Classification	Inheritance
torsion dystonia 2	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
complex movement disorder with or without neurodevelopmental features	Definitive	AR

Mondo (1): torsion dystonia 2 (MONDO:0009141)

Orphanet (1): Primary dystonia, DYT2 type (Orphanet:99657)

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538006	Dystonia musculorum deformans type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases methylation	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
propionaldehyde	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
butyraldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Ivermectin	decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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