SEZ6

Summary

SEZ6 (seizure related 6 homolog, HGNC:15955) is a protein-coding gene on chromosome 17q11.2, encoding Seizure protein 6 homolog (Q53EL9). May play a role in cell-cell recognition and in neuronal membrane signaling.

The protein encoded by this gene is thought to contain five cysteine-rich motifs that are similar to sushi domains, as well as two domains similar to the amino terminal half of the CUB (for complement C1r/C1s, Uegf, Bmp1) domain. Mutations in this gene have been associated with febrile seizures.

Source: NCBI Gene 124925 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nonsyndromic genetic hearing loss (Limited, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 147 total — 1 likely-pathogenic
• MANE Select transcript: NM_178860

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15955
Approved symbol	SEZ6
Name	seizure related 6 homolog
Location	17q11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000063015
Ensembl biotype	protein_coding
OMIM	616666
Entrez	124925

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000317338, ENST00000360295, ENST00000442608, ENST00000535262, ENST00000539265, ENST00000540419, ENST00000540632, ENST00000544224, ENST00000585644

RefSeq mRNA: 3 — MANE Select: NM_178860 NM_001098635, NM_001290202, NM_178860

CCDS: CCDS45638, CCDS45639

Canonical transcript exons

ENST00000317338 — 17 exons

Exon	Start	End
ENSE00000866390	28960805	28960973
ENSE00001113981	28979680	28979813
ENSE00001124930	28960505	28960671
ENSE00001124943	28963962	28964147
ENSE00001217316	28959698	28959892
ENSE00001217752	28969757	28969952
ENSE00002321182	28954905	28955994
ENSE00002382621	28981371	28982039
ENSE00002923090	29005815	29006033
ENSE00003529229	28956719	28956757
ENSE00003570163	28956159	28956261
ENSE00003575114	28957947	28958141
ENSE00003606634	28957348	28957539
ENSE00003622601	28959025	28959221
ENSE00003635047	28959334	28959472
ENSE00003654305	28956350	28956467
ENSE00003682642	28957045	28957242

Expression profiles

Bgee: expression breadth ubiquitous, 167 present calls, max score 99.37.

FANTOM5 (CAGE): breadth broad, TPM avg 8.4372 / max 2025.3250, expressed in 302 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
165110	7.8374	248
165105	0.2100	71
165108	0.1185	40
165106	0.1091	34
165107	0.0654	27
165109	0.0384	18
165104	0.0347	14
165111	0.0161	6
165112	0.0075	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.37	gold quality
ganglionic eminence	UBERON:0004023	99.23	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.60	gold quality
cerebellar hemisphere	UBERON:0002245	97.40	gold quality
cerebellar cortex	UBERON:0002129	97.34	gold quality
cerebellum	UBERON:0002037	96.30	gold quality
nucleus accumbens	UBERON:0001882	95.66	gold quality
caudate nucleus	UBERON:0001873	94.43	gold quality
putamen	UBERON:0001874	93.82	gold quality
prefrontal cortex	UBERON:0000451	90.72	gold quality
right frontal lobe	UBERON:0002810	90.72	gold quality
anterior cingulate cortex	UBERON:0009835	89.58	gold quality
amygdala	UBERON:0001876	89.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.01	gold quality
hypothalamus	UBERON:0001898	88.82	gold quality
cardiac muscle of right atrium	UBERON:0003379	88.73	gold quality
frontal cortex	UBERON:0001870	88.59	gold quality
left ventricle myocardium	UBERON:0006566	88.58	gold quality
neocortex	UBERON:0001950	88.52	gold quality
brain	UBERON:0000955	88.14	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.00	gold quality
forebrain	UBERON:0001890	87.77	gold quality
cerebral cortex	UBERON:0000956	87.32	gold quality
temporal lobe	UBERON:0001871	86.33	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.34	gold quality
Ammon’s horn	UBERON:0001954	85.00	gold quality
entorhinal cortex	UBERON:0002728	84.32	gold quality
myocardium	UBERON:0002349	83.33	gold quality
cerebellar vermis	UBERON:0004720	82.85	gold quality
superior frontal gyrus	UBERON:0002661	82.56	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-7	yes	400.55
E-HCAD-5	yes	51.34
E-ANND-3	yes	3.06
E-GEOD-75140	no	1304.17

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

76 targeting SEZ6, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4267	99.96	66.53	2368
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-4273	99.45	67.93	1206
HSA-MIR-4666A-5P	99.41	69.72	1887
HSA-MIR-5580-5P	99.38	66.96	1139

Literature-anchored findings (GeneRIF, showing 4)

• The human SEZ-6 gene is related to the occurrence and development of FS and may be a novel candidate gene for epilepsy. Screening for mutations in SEZ-6 may be valuable in predicting FS recurrence or the development of epilepsy. (PMID:17086543)
• Study describes a targeted exome sequencing analysis of a large Italian kindred with Alzheimer disease, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology. (PMID:30309378)
• ADAMTS1, MPDZ, MVD, and SEZ6: candidate genes for autosomal recessive nonsyndromic hearing impairment. (PMID:34135477)
• Potential genetic biomarkers predict adverse pregnancy outcome during early and mid-pregnancy in women with systemic lupus erythematosus. (PMID:36465614)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	sez6b	ENSDARG00000079414
danio_rerio	sez6a	ENSDARG00000100876
mus_musculus	Sez6	ENSMUSG00000000632
rattus_norvegicus	Sez6	ENSRNOG00000009350

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPA (ENSG00000123838), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), CFHR5 (ENSG00000134389), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Seizure protein 6 homolog — Q53EL9 (reviewed: Q53EL9)

All UniProt accessions (7): Q53EL9, A0A0A0MSU7, H0YF95, H0YFT6, H0YFX0, H0YGK0, K7ELJ4

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in cell-cell recognition and in neuronal membrane signaling. Seems to be important for the achievement of the necessary balance between dendrite elongation and branching during the elaboration of a complex dendritic arbor. Involved in the development of appropriate excitatory synaptic connectivity.

Subcellular location. Cell membrane.

Post-translational modifications. Glycosylated.

Similarity. Belongs to the SEZ6 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q53EL9-1	1	yes
Q53EL9-2	2
Q53EL9-3	3
Q53EL9-4	4, SEZ6b

RefSeq proteins (3): NP_001092105, NP_001277131, NP_849191* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR000859	CUB_dom	Domain
IPR035914	Sperma_CUB_dom_sf	Homologous_superfamily
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR051277	SEZ6_CSMD_C4BPB_Regulators	Family

Pfam: PF00084, PF00431

UniProt features (56 total): disulfide bond 12, sequence conflict 8, domain 7, sequence variant 7, region of interest 6, glycosylation site 4, splice variant 4, compositionally biased region 3, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q53EL9-F1	70.43	0.29

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 (12): 357–397, 383–412, 416–443, 532–574, 559–589, 593–619, 710–752, 738–765, 771–813, 799–830, 838–880, 866–895

Glycosylation sites (4): 289, 399, 436, 541

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 149 (showing top): AHRARNT_01, GOBP_DENDRITE_DEVELOPMENT, RNGTGGGC_UNKNOWN, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_METENCEPHALON_DEVELOPMENT, BENPORATH_ES_WITH_H3K27ME3, MYOGENIN_Q6, GOBP_BEHAVIOR, E2F4DP1_01, NKX25_02, GCANCTGNY_MYOD_Q6, GOBP_ADULT_BEHAVIOR, TATTATA_MIR374, GOBP_NEUROGENESIS, GOBP_ADULT_LOCOMOTORY_BEHAVIOR

GO Biological Process (5): adult locomotory behavior (GO:0008344), cerebellar Purkinje cell layer development (GO:0021680), regulation of dendrite development (GO:0050773), synapse maturation (GO:0060074), excitatory postsynaptic potential (GO:0060079)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (8): endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), neuronal cell body (GO:0043025), dendritic spine (GO:0043197), dendritic shaft (GO:0043198), perinuclear region of cytoplasm (GO:0048471), apical dendrite (GO:0097440), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
dendrite	3
cellular anatomical structure	3
cytoplasm	2
locomotory behavior	1
adult behavior	1
cerebellar cortex development	1
anatomical structure development	1
regulation of neuron projection development	1
dendrite development	1
regulation of developmental process	1
nervous system development	1
developmental maturation	1
synapse organization	1
regulation of postsynaptic membrane potential	1
chemical synaptic transmission, postsynaptic	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
somatodendritic compartment	1
cell body	1
neuron spine	1
postsynapse	1

Protein interactions and networks

STRING

2007 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SEZ6	C4A	P01028	479
SEZ6	BACE1	P56817	463
SEZ6	SHISAL2A	Q6UWV7	448
SEZ6	C4A	P01028	445
SEZ6	SDF2	Q99470	435
SEZ6	APLP1	P51693	428
SEZ6	SKAP1	Q86WV1	398
SEZ6	MPDZ	O75970	386
SEZ6	PHF12	Q96QT6	386
SEZ6	WSCD1	Q658N2	382
SEZ6	ATP2A3	Q93084	379
SEZ6	TBC1D32	Q96NH3	379
SEZ6	BACE2	Q9Y5Z0	378
SEZ6	CD6	P30203	374
SEZ6	LHX3	Q9UBR4	372

IntAct

7 interactions, top by confidence:

A	B	Type	Score
SEZ6	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
CHDH	SEZ6	psi-mi:“MI:0915”(physical association)	0.370
SEZ6	METAP2	psi-mi:“MI:0914”(association)	0.350
SEZ6	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
TNK2	SEZ6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): SEZ6 (Affinity Capture-RNA), UBQLN2 (Two-hybrid), RPL23 (Affinity Capture-MS), SNX17 (Affinity Capture-MS), METAP2 (Affinity Capture-MS), LMF1 (Affinity Capture-MS), SEZ6 (Affinity Capture-MS), SEZ6 (Co-fractionation), SEZ6 (Co-fractionation), SEZ6 (Co-fractionation), SEZ6 (Two-hybrid)

ESM2 similar proteins: A0JNA2, A4FUY1, C0HL12, O14514, O19131, O60241, O75325, P0C5H6, P15151, P32506, P32507, P70225, P98095, Q05BQ1, Q13477, Q14626, Q14CZ8, Q29RN8, Q3UHD1, Q4V9Z5, Q53EL9, Q5DRQ8, Q5R7Y0, Q5RF19, Q5STE3, Q63148, Q64385, Q6AX42, Q6BAA4, Q6MZW2, Q6UWL2, Q6UWL6, Q6UXD5, Q6WN34, Q7TSK2, Q7TSU7, Q8BHA1, Q8BQC3, Q8CGM1, Q8IVU1

Diamond homologs: A0A182C2Z2, A0JNA2, B3EX01, E7FEC4, O08569, O19124, O57254, O62685, O62837, O88174, P08174, P0DTN2, P15529, P21115, P24083, P24084, P36980, P49457, P79138, P81475, Q01227, Q07968, Q28085, Q29RN8, Q4V9Z5, Q53EL9, Q5R4D0, Q5R8M2, Q5VX71, Q60736, Q63515, Q6AX42, Q6P1D5, Q6UXD5, Q7TSK2, Q7Z408, Q8BH32, Q9BYH1, Q9JF44, Q9W332

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	117
Likely benign	9
Benign	10

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
208383	NM_178860.5(SEZ6):c.678_686del (p.Thr227_Thr229del)	Likely pathogenic

SpliceAI

2799 predictions. Top by Δscore:

Variant	Effect	Δscore
17:28956157:A:AC	donor_gain	1.0000
17:28956157:ACT:A	donor_gain	1.0000
17:28956158:C:CT	donor_gain	1.0000
17:28956158:CT:C	donor_gain	1.0000
17:28956158:CTC:C	donor_gain	1.0000
17:28956158:CTCCA:C	donor_gain	1.0000
17:28956262:C:CA	acceptor_loss	1.0000
17:28956262:C:CC	acceptor_gain	1.0000
17:28956346:TCAC:T	donor_loss	1.0000
17:28956348:A:AC	donor_gain	1.0000
17:28956348:AC:A	donor_gain	1.0000
17:28956349:C:CC	donor_gain	1.0000
17:28956349:CC:C	donor_gain	1.0000
17:28956349:CCT:C	donor_gain	1.0000
17:28956349:CCTG:C	donor_gain	1.0000
17:28956349:CCTGG:C	donor_gain	1.0000
17:28956463:GGCAA:G	acceptor_gain	1.0000
17:28956464:GCAA:G	acceptor_gain	1.0000
17:28956465:CAA:C	acceptor_gain	1.0000
17:28956465:CAAC:C	acceptor_gain	1.0000
17:28956466:AA:A	acceptor_gain	1.0000
17:28956468:C:CC	acceptor_gain	1.0000
17:28956713:ACTT:A	donor_loss	1.0000
17:28956715:TTA:T	donor_loss	1.0000
17:28956716:TA:T	donor_loss	1.0000
17:28956717:A:AC	donor_gain	1.0000
17:28956717:A:AT	donor_loss	1.0000
17:28956718:C:CC	donor_gain	1.0000
17:28956718:C:G	donor_loss	1.0000
17:28957243:C:CC	acceptor_gain	1.0000

AlphaMissense

6450 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:28957373:C:A	W823C	1.000
17:28957373:C:G	W823C	1.000
17:28957975:C:A	W758C	1.000
17:28957975:C:G	W758C	1.000
17:28957993:G:C	C752W	1.000
17:28957994:C:G	C752S	1.000
17:28957995:A:G	C752R	1.000
17:28957995:A:T	C752S	1.000
17:28958121:A:G	C710R	1.000
17:28959381:C:A	W621C	1.000
17:28959381:C:G	W621C	1.000
17:28959389:A:G	C619R	1.000
17:28959703:C:G	C589S	1.000
17:28959704:A:T	C589S	1.000
17:28959723:C:A	W582C	1.000
17:28959723:C:G	W582C	1.000
17:28959724:C:G	W582S	1.000
17:28959725:A:G	W582R	1.000
17:28959725:A:T	W582R	1.000
17:28959748:C:G	C574S	1.000
17:28959749:A:G	C574R	1.000
17:28959749:A:T	C574S	1.000
17:28959793:C:T	C559Y	1.000
17:28960879:C:A	W445C	1.000
17:28960879:C:G	W445C	1.000
17:28963987:C:A	W405C	1.000
17:28963987:C:G	W405C	1.000
17:28957375:A:G	W823R	0.999
17:28957375:A:T	W823R	0.999
17:28957955:C:G	C765S	0.999

dbSNP variants (sampled 300 via entrez): RS1000005510 (17:29002979 G>C), RS1000064334 (17:28989799 G>A), RS1000143657 (17:28992690 A>G), RS1000190251 (17:28976538 G>A), RS1000194481 (17:28987441 G>C), RS1000217907 (17:29001350 G>A), RS1000248191 (17:29006051 G>A,C,T), RS1000357242 (17:28990631 C>T), RS1000384161 (17:28995556 G>A), RS1000409582 (17:28990095 A>T), RS1000498408 (17:29007036 T>G), RS1000510977 (17:28963007 C>T), RS1000543570 (17:28963482 C>G,T), RS1000547068 (17:29007327 G>T), RS1000563375 (17:28999894 T>C)

Disease associations

OMIM: gene MIM:616666 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	Autosomal recessive

Mondo (2): childhood-onset schizophrenia (MONDO:0957430), nonsyndromic genetic hearing loss (MONDO:0019497)

Orphanet (1): Childhood-onset schizophrenia (Orphanet:641496)

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006231_8	Mean arterial pressure	2.000000e-07
GCST90093325_17	Language functional connectivity	5.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006340	mean arterial pressure
EFO:0007797	language measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	increases expression, affects cotreatment	3
Valproic Acid	increases expression, affects cotreatment	3
bisphenol A	decreases methylation, increases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
belinostat	increases expression, affects cotreatment	2
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
Aflatoxin B1	decreases methylation	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
arsenite	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
mono(carboxy-isooctyl)phthalate	increases abundance, increases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diethylhexyl Phthalate	decreases expression	1
Estradiol	increases expression	1
Methotrexate	decreases expression	1
Ozone	increases abundance, affects expression	1
Phthalic Acids	increases abundance, increases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Silicon Dioxide	increases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Tunicamycin	increases expression	1
Zearalenone	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations