CBLN1

Summary

CBLN1 (cerebellin 1 precursor, HGNC:1543) is a protein-coding gene on chromosome 16q12.1, encoding Cerebellin-1 (P23435). Required for synapse integrity and synaptic plasticity.

This gene encodes a cerebellum-specific precursor protein, precerebellin, with similarity to the globular (non-collagen-like) domain of complement component C1qB. Precerebellin is processed to give rise to several derivatives, including the hexadecapeptide, cerebellin, which is highly enriched in postsynaptic structures of Purkinje cells. Cerebellin has also been found in human and rat adrenals, where it has been shown to enhance the secretory activity of this gland.

Source: NCBI Gene 869 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 19 total
• MANE Select transcript: NM_004352

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1543
Approved symbol	CBLN1
Name	cerebellin 1 precursor
Location	16q12.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000102924
Ensembl biotype	protein_coding
OMIM	600432
Entrez	869

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 nonsense_mediated_decay

ENST00000219197, ENST00000564786

RefSeq mRNA: 1 — MANE Select: NM_004352 NM_004352

CCDS: CCDS10736

Canonical transcript exons

ENST00000219197 — 3 exons

Exon	Start	End
ENSE00000682965	49280923	49281042
ENSE00001301806	49277917	49279601
ENSE00001302831	49281202	49281838

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 98.64.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0218 / max 359.5144, expressed in 238 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
157276	0.6319	187
157275	0.3774	102
157274	0.0125	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar cortex	UBERON:0002129	98.64	gold quality
cerebellar hemisphere	UBERON:0002245	98.62	gold quality
cerebellum	UBERON:0002037	98.34	gold quality
paraflocculus	UBERON:0005351	98.12	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.98	gold quality
cerebellar vermis	UBERON:0004720	96.81	gold quality
sperm	CL:0000019	95.67	gold quality
male germ cell	CL:0000015	91.71	gold quality
left testis	UBERON:0004533	88.16	gold quality
right testis	UBERON:0004534	87.11	gold quality
testis	UBERON:0000473	85.57	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.96	gold quality
hypothalamus	UBERON:0001898	84.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.69	gold quality
cortical plate	UBERON:0005343	80.49	gold quality
gall bladder	UBERON:0002110	78.23	gold quality
adult organism	UBERON:0007023	77.80	gold quality
pons	UBERON:0000988	77.29	gold quality
substantia nigra	UBERON:0002038	74.27	gold quality
prefrontal cortex	UBERON:0000451	73.88	gold quality
ganglionic eminence	UBERON:0004023	73.67	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	73.34	gold quality
substantia nigra pars reticulata	UBERON:0001966	72.62	gold quality
midbrain	UBERON:0001891	71.25	gold quality
right frontal lobe	UBERON:0002810	71.02	gold quality
heart left ventricle	UBERON:0002084	70.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	70.11	gold quality
spinal cord	UBERON:0002240	70.07	gold quality
cardiac ventricle	UBERON:0002082	69.72	gold quality
apex of heart	UBERON:0002098	69.60	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

91 targeting CBLN1, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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-1468-3P	99.96	72.74	3797
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1323	99.83	69.89	2471

Literature-anchored findings (GeneRIF, showing 3)

• Cbln1 and Cbln2 are co-expressed in the endolysosomal compartment of the thalamic neurons responsible for the synaptic alterations in striatum of Cbln1-null mice. (PMID:22117778)
• Serum amphiregulin and cerebellin-1 levels in severe preeclampsia. (PMID:31630583)
• Family-Based Cohort Association Study of PRKCB1, CBLN1 and KCNMB4 Gene Polymorphisms and Autism in Polish Population. (PMID:34562210)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbln1	ENSDARG00000057296
mus_musculus	Cbln1	ENSMUSG00000031654
rattus_norvegicus	Cbln1	ENSRNOG00000000010

Paralogs (3): CBLN4 (ENSG00000054803), CBLN3 (ENSG00000139899), CBLN2 (ENSG00000141668)

Protein

Protein identifiers

Cerebellin-1 — P23435 (reviewed: P23435)

Alternative names: Precerebellin

All UniProt accessions (2): P23435, H3BQD0

UniProt curated annotations — full annotation on UniProt →

Function. Required for synapse integrity and synaptic plasticity. During cerebellar synapse formation, essential for the matching and maintenance of pre- and post-synaptic elements at parallel fiber-Purkinje cell synapses, the establishment of the proper pattern of climbing fiber-Purkinje cell innervation, and induction of long-term depression at parallel fiber-Purkinje cell synapses. Plays a role as a synaptic organizer that acts bidirectionally on both pre- and post-synaptic components. On the one hand induces accumulation of synaptic vesicles in the pre-synaptic part by binding with NRXN1 and in other hand induces clustering of GRID2 and its associated proteins at the post-synaptic site through association of GRID2. NRXN1-CBLN1-GRID2 complex directly induces parallel fiber protrusions that encapsulate spines of Purkinje cells leading to accumulation of GRID2 and synaptic vesicles. Required for CBLN3 export from the endoplasmic reticulum and secretion. NRXN1-CBLN1-GRID2 complex mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis. Essential for long-term maintenance but not establishment of excitatory synapses. Inhibits the formation and function of inhibitory GABAergic synapses in cerebellar Purkinje cells. The cerebellin peptide exerts neuromodulatory functions. Directly stimulates norepinephrine release via the adenylate cyclase/PKA-dependent signaling pathway; and indirectly enhances adrenocortical secretion in vivo, through a paracrine mechanism involving medullary catecholamine release.

Subunit / interactions. Homohexamer; disulfide-linked homotrimers. The trimers associate via N-terminal cysteine residues to form disulfide-linked hexamers. May form oligomers with CBLN2, CBLN3 AND CBLN4 prior to secretion. Once secreted, does not interact with other CBLN family members. Interacts with GRID1. Interacts with NRXN1 and NRXN2 long (alpha) and short (beta) isoforms produced by alternative promoter usage. Competes with NLGN1 for NRXN1-binding. Weakly interacts with NRXN3 short isoform and not at all with NRXN3 long isoform. Interacts (via C1q domain) with GRID2; GRID2-binding is calcium-independent; CBLN1 hexamers anchor GRID2 N-terminal domain dimers to monomeric NRXN1 isoform beta; promotes synaptogenesis and mediates the D-Serine-dependent long term depression signals and AMPA receptor endocytosis. Interacts with OTOL1.

Subcellular location. Secreted. Postsynaptic cell membrane.

Tissue specificity. In the Purkinje cells postsynaptic structures. In the cerebellum, cerebellin is much less abundant than [des-Ser1]-cerebellin.

Post-translational modifications. The proteolytic processing to yield cerebellin seems to occur either prior to the secretion by presynaptic neurons and subsequent oligomerization or in some other location after release of the mature protein. Sialoglycoprotein.

RefSeq proteins (1): NP_004343* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001073	C1q_dom	Domain
IPR008983	Tumour_necrosis_fac-like_dom	Homologous_superfamily
IPR050822	Cerebellin_Synaptic_Org	Family

Pfam: PF00386

UniProt features (29 total): strand 10, mutagenesis site 5, region of interest 3, disulfide bond 2, peptide 2, glycosylation site 2, signal peptide 1, chain 1, helix 1, turn 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
5KC5	X-RAY DIFFRACTION	2.35
5KC6	X-RAY DIFFRACTION	2.8
5KCA	X-RAY DIFFRACTION	3.1
5KC7	X-RAY DIFFRACTION	7.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P23435-F1	81.22	0.53

Functional residue map

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

Disulfide bonds (2): 34, 38

Glycosylation sites (2): 23, 79

Mutagenesis-validated functional residues (5):

Position	Phenotype
34	abolishes hexamer formation; when associated with s-38. abolishes interaction with nrxn1; when associated with s-38. abo
38	abolishes hexamer formation; when associated with s-34. abolishes interaction with nrxn1 isoform 3b; when associated wit
122	abolishes grid2 interaction.; when associated with a-124 and a-147.
124	abolishes grid2 interaction.; when associated with a-122 and a-147.
147	abolishes grid2 interaction.; when associated with a-122 and a-124.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 237 (showing top): GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, MODULE_274, MODULE_255, GOBP_SYNAPSE_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_SYNAPSE_ASSEMBLY, MODULE_317, GOBP_CEREBELLAR_CORTEX_MORPHOGENESIS, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_NEGATIVE_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (16): heterophilic cell-cell adhesion (GO:0007157), chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), synapse assembly (GO:0007416), protein secretion (GO:0009306), cerebellar granule cell differentiation (GO:0021707), synapse organization (GO:0050808), establishment of localization in cell (GO:0051649), positive regulation of synapse assembly (GO:0051965), negative regulation of excitatory postsynaptic potential (GO:0090394), regulation of postsynaptic density assembly (GO:0099151), trans-synaptic signaling, modulating synaptic transmission (GO:0099550), maintenance of synapse structure (GO:0099558), positive regulation of long-term synaptic depression (GO:1900454), regulation of presynapse assembly (GO:1905606), negative regulation of inhibitory synapse assembly (GO:1905703)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): extracellular region (GO:0005576), extracellular matrix (GO:0031012), synaptic cleft (GO:0043083), postsynaptic membrane (GO:0045211), parallel fiber to Purkinje cell synapse (GO:0098688), trans-synaptic protein complex (GO:0098820), glutamatergic synapse (GO:0098978), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
synapse organization	2
regulation of synapse assembly	2
cell-cell adhesion	1
anterograde trans-synaptic signaling	1
system development	1
nervous system development	1
cell junction assembly	1
protein transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
cell differentiation in hindbrain	1
cerebellar granular layer formation	1
central nervous system neuron differentiation	1
glutamatergic neuron differentiation	1
cell junction organization	1
establishment of localization	1
cellular localization	1
synapse assembly	1
positive regulation of nervous system development	1
positive regulation of cell junction assembly	1
negative regulation of biological process	1
excitatory postsynaptic potential	1
modulation of excitatory postsynaptic potential	1
postsynaptic density assembly	1
regulation of postsynaptic specialization assembly	1
regulation of excitatory synapse assembly	1
regulation of postsynaptic density organization	1
chemical synaptic transmission	1
modulation of chemical synaptic transmission	1
trans-synaptic signaling	1
cell junction maintenance	1
positive regulation of biological process	1
long-term synaptic depression	1
regulation of long-term synaptic depression	1
presynapse assembly	1
regulation of presynapse organization	1
negative regulation of synapse assembly	1
inhibitory synapse assembly	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

4 interactions, top by confidence:

A	B	Type	Score
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (2): CBLN1 (Affinity Capture-MS), CBLN1 (Affinity Capture-MS)

ESM2 similar proteins: A1A5X5, O77764, O95150, P01375, P02746, P13296, P14106, P23383, P23435, P23563, P29553, P31720, P31721, P31722, P36939, P50591, P50592, P51742, P51743, P59684, P59693, P59694, P63182, P86437, P98087, Q06599, Q15848, Q17QF9, Q1G1A2, Q2KIV9, Q2MH05, Q3T1I2, Q3Y5Z3, Q5UBV8, Q5XIG2, Q60994, Q6IR41, Q8BGU2, Q8BME9, Q8HZD9

Diamond homologs: A0A060WQA3, A5PN28, A6NHN0, B2RNN3, O75973, O88992, P02745, P02746, P02747, P08125, P0C862, P14282, P23206, P23435, P25067, P25318, P27658, P31720, P63182, P83371, P86437, P98085, P98086, P98087, Q00780, Q02105, Q03692, Q05306, Q05A80, Q0II24, Q15848, Q17QF9, Q2KIV9, Q3Y5Z3, Q4ZJM7, Q4ZJM9, Q4ZJN1, Q5E9E3, Q5FVH0, Q5RJ80

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

408 predictions. Top by Δscore:

Variant	Effect	Δscore
16:49279600:ACCT:A	acceptor_loss	1.0000
16:49281197:CTCA:C	donor_loss	1.0000
16:49281198:TCA:T	donor_loss	1.0000
16:49281199:CACCT:C	donor_loss	1.0000
16:49281200:ACCT:A	donor_loss	1.0000
16:49281201:C:CA	donor_loss	1.0000
16:49279445:T:TA	donor_gain	0.9900
16:49279597:CTCAC:C	acceptor_gain	0.9900
16:49279598:TCAC:T	acceptor_gain	0.9900
16:49279599:CAC:C	acceptor_gain	0.9900
16:49279599:CACC:C	acceptor_gain	0.9900
16:49279602:C:CC	acceptor_gain	0.9900
16:49281200:A:AC	donor_gain	0.9900
16:49281201:C:CC	donor_gain	0.9900
16:49281605:T:TA	donor_gain	0.9900
16:49280918:CTGA:C	donor_loss	0.9800
16:49280919:TGA:T	donor_loss	0.9800
16:49280921:A:AT	donor_loss	0.9800
16:49280922:C:T	donor_loss	0.9800
16:49280952:C:CT	donor_gain	0.9800
16:49281201:CCTGG:C	donor_gain	0.9800
16:49281559:G:C	donor_gain	0.9800
16:49279600:AC:A	acceptor_gain	0.9700
16:49279601:CC:C	acceptor_gain	0.9700
16:49280495:T:TA	donor_gain	0.9700
16:49280923:C:G	donor_loss	0.9700
16:49281200:AC:A	donor_gain	0.9700
16:49281201:CC:C	donor_gain	0.9700
16:49281201:CCT:C	donor_gain	0.9700
16:49281237:T:C	donor_gain	0.9700

AlphaMissense

1256 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:49279426:C:T	G187E	1.000
16:49279430:A:G	S186P	1.000
16:49279438:G:C	S183W	1.000
16:49279465:C:A	G174V	1.000
16:49279466:C:G	G174R	1.000
16:49279466:C:T	G174R	1.000
16:49279480:A:G	L169P	1.000
16:49279480:A:T	L169H	1.000
16:49279528:G:T	A153D	1.000
16:49279560:G:C	F142L	1.000
16:49279560:G:T	F142L	1.000
16:49279561:A:C	F142C	1.000
16:49279562:A:G	F142L	1.000
16:49279594:A:G	L131P	1.000
16:49280948:T:A	K120I	1.000
16:49280973:A:C	Y112D	1.000
16:49280978:C:T	G110E	1.000
16:49280979:C:A	G110W	1.000
16:49280979:C:G	G110R	1.000
16:49280979:C:T	G110R	1.000
16:49280996:A:G	F104S	1.000
16:49281262:C:A	R68S	1.000
16:49281262:C:G	R68S	1.000
16:49281263:C:A	R68M	1.000
16:49281263:C:G	R68T	1.000
16:49281273:A:G	S65P	1.000
16:49281274:G:C	F64L	1.000
16:49281274:G:T	F64L	1.000
16:49281275:A:G	F64S	1.000
16:49281276:A:G	F64L	1.000

dbSNP variants (sampled 300 via entrez): RS1000850415 (16:49280270 C>G), RS1001006856 (16:49280173 T>C), RS1001291487 (16:49278203 T>C), RS1001516443 (16:49277630 G>A), RS1001617695 (16:49278111 T>G), RS1002070332 (16:49283217 C>A), RS1003497714 (16:49283032 A>C,G), RS1005117168 (16:49280450 C>T), RS1005169490 (16:49280653 T>C), RS1005506284 (16:49279263 C>A,T), RS1005908549 (16:49283719 T>G), RS1006468700 (16:49278210 G>A), RS1007347782 (16:49283375 T>C), RS1007547309 (16:49282350 G>T), RS1007583273 (16:49282584 C>G)

Disease associations

OMIM: gene MIM:600432 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002228_2	Social autistic-like traits	2.000000e-06
GCST002783_264	Body mass index	9.000000e-09
GCST002783_619	Body mass index	7.000000e-08
GCST004904_121	Body mass index	8.000000e-11
GCST005024_32	Pursuit maintenance gain	9.000000e-06
GCST006077_5	Branched-chain amino acid levels (Isoleucine)	4.000000e-08
GCST006585_2767	Blood protein levels	4.000000e-08
GCST009719_12	Allergic rhinitis	4.000000e-09
GCST010988_44	Adult body size	1.000000e-08
GCST010989_10	Body size at age 10	4.000000e-09
GCST012047_16	Fasting glucose	1.000000e-07

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0005426	autism spectrum disorder symptom
EFO:0004340	body mass index
EFO:0008433	pursuit maintenance gain measurement
EFO:0005134	amino acid measurement
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	6
bisphenol A	increases expression	2
entinostat	increases expression, affects cotreatment	2
bisphenol F	increases methylation	1
decabromobiphenyl ether	increases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
tetrabromobisphenol A	increases expression	1
tetrachlorodian	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression	1
Phthalic Acids	decreases methylation	1
Triclosan	increases expression	1
Zearalenone	increases expression	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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