SHISA6

Summary

SHISA6 (shisa family member 6, HGNC:34491) is a protein-coding gene on chromosome 17p12, encoding Protein shisa-6 (Q6ZSJ9). Involved in maintenance of high-frequency synaptic transmission at hippocampal CA3-CA1 synapses.

Predicted to enable ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including excitatory chemical synaptic transmission; modulation of chemical synaptic transmission; and negative regulation of canonical Wnt signaling pathway. Predicted to be located in asymmetric, glutamatergic, excitatory synapse. Predicted to be part of AMPA glutamate receptor complex. Predicted to be active in dendritic spine membrane; glutamatergic synapse; and postsynaptic density membrane.

Source: NCBI Gene 388336 — RefSeq curated summary.

At a glance

• GWAS associations: 14
• Clinical variants (ClinVar): 113 total
• MANE Select transcript: NM_207386

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:34491
Approved symbol	SHISA6
Name	shisa family member 6
Location	17p12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ45455
Ensembl gene	ENSG00000188803
Ensembl biotype	protein_coding
OMIM	617327
Entrez	388336

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000343478, ENST00000409168, ENST00000432116, ENST00000441885

RefSeq mRNA: 3 — MANE Select: NM_207386 NM_001173461, NM_001173462, NM_207386

CCDS: CCDS45615, CCDS54089, CCDS54090

Canonical transcript exons

ENST00000441885 — 6 exons

Exon	Start	End
ENSE00001379363	11555740	11555892
ENSE00001482411	11379414	11379509
ENSE00001537633	11557754	11564063
ENSE00001738478	11551896	11551952
ENSE00003704480	11263366	11263526
ENSE00003895844	11241213	11242060

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 90.31.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1504 / max 10.2850, expressed in 73 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
159601	0.0897	51
159602	0.0607	33

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	90.31	gold quality
cerebellar vermis	UBERON:0004720	87.40	gold quality
cortical plate	UBERON:0005343	84.39	gold quality
medulla oblongata	UBERON:0001896	83.32	gold quality
superior vestibular nucleus	UBERON:0007227	83.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.92	gold quality
Ammon’s horn	UBERON:0001954	82.87	gold quality
substantia nigra	UBERON:0002038	81.95	gold quality
hypothalamus	UBERON:0001898	81.21	gold quality
midbrain	UBERON:0001891	80.84	gold quality
spinal cord	UBERON:0002240	80.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	79.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	79.18	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	79.13	gold quality
cerebellum	UBERON:0002037	78.00	gold quality
cerebellar cortex	UBERON:0002129	77.18	gold quality
amygdala	UBERON:0001876	77.12	gold quality
cerebellar hemisphere	UBERON:0002245	76.97	gold quality
substantia nigra pars compacta	UBERON:0001965	76.15	gold quality
ventral tegmental area	UBERON:0002691	76.09	gold quality
tibial nerve	UBERON:0001323	75.97	gold quality
primary visual cortex	UBERON:0002436	75.65	gold quality
endocervix	UBERON:0000458	75.47	gold quality
anterior cingulate cortex	UBERON:0009835	74.85	gold quality
medial globus pallidus	UBERON:0002477	74.75	gold quality
temporal lobe	UBERON:0001871	74.21	gold quality
seminal vesicle	UBERON:0000998	73.89	gold quality
cerebral cortex	UBERON:0000956	73.85	gold quality
dorsal plus ventral thalamus	UBERON:0001897	73.66	gold quality
dorsal root ganglion	UBERON:0000044	73.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

285 targeting SHISA6, 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-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-3173-3P	99.98	66.49	1217

Literature-anchored findings (GeneRIF, showing 1)

• Genetic variants in the SHISA6 gene are associated with delayed cognitive impairment in two family datasets. (PMID:35490390)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	shisa6	ENSDARG00000115501
mus_musculus	Shisa6	ENSMUSG00000053930
rattus_norvegicus	Shisa6	ENSRNOG00000029012

Paralogs (3): SHISA7 (ENSG00000187902), SHISA8 (ENSG00000234965), SHISA9 (ENSG00000237515)

Protein

Protein identifiers

Protein shisa-6 — Q6ZSJ9 (reviewed: Q6ZSJ9)

All UniProt accessions (2): Q6ZSJ9, V9GZ25

UniProt curated annotations — full annotation on UniProt →

Function. Involved in maintenance of high-frequency synaptic transmission at hippocampal CA3-CA1 synapses. Regulates AMPA-type glutamate receptor (AMPAR) immobilization at postsynaptic density keeping the channels in an activated state in the presence of glutamate and preventing synaptic depression. May play a role in self-renewal and differentiation of spermatogonial stem cells by inhibiting canonical Wnt signaling pathway.

Subunit / interactions. Component of the postsynaptic hippocampal AMPA-type glutamate receptor (AMPAR) complex, at least composed of pore forming AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7. Interacts (via PDZ-binding motif) with DLG4/PSD-95 (via PDZ domain); the interaction is direct.

Subcellular location. Membrane. Postsynaptic density.

Tissue specificity. Expressed in the developing ventral mesencephalon.

Domain organisation. The PDZ-binding motif interacts with PDZ-domain of scaffolding protein DLG4.

Similarity. Belongs to the shisa family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6ZSJ9-1	1	yes
Q6ZSJ9-2	2
Q6ZSJ9-3	3

RefSeq proteins (3): NP_001166932, NP_001166933, NP_997269* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026910	Shisa	Family
IPR053891	Shisa_N	Domain

Pfam: PF13908

UniProt features (23 total): modified residue 5, region of interest 4, compositionally biased region 2, glycosylation site 2, splice variant 2, topological domain 2, sequence conflict 2, signal peptide 1, chain 1, transmembrane region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZSJ9-F1	55.97	0.13

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 (5): 391, 397, 409, 433, 477

Glycosylation sites (2): 32, 59

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 244 (showing top): RNGTGGGC_UNKNOWN, chr17p12, BENPORATH_ES_WITH_H3K27ME3, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, AAGCCAT_MIR135A_MIR135B, GOBP_REGULATION_OF_SHORT_TERM_NEURONAL_SYNAPTIC_PLASTICITY, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_MALE_GAMETE_GENERATION, CAGCTG_AP4_Q5, SREBP1_02, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, GOBP_CANONICAL_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION

GO Biological Process (7): spermatogenesis (GO:0007283), Wnt signaling pathway (GO:0016055), regulation of short-term neuronal synaptic plasticity (GO:0048172), negative regulation of canonical Wnt signaling pathway (GO:0090090), postsynaptic neurotransmitter receptor diffusion trapping (GO:0098970), excitatory chemical synaptic transmission (GO:0098976), regulation of AMPA glutamate receptor clustering (GO:1904717)

GO Molecular Function (3): PDZ domain binding (GO:0030165), ionotropic glutamate receptor binding (GO:0035255), protein binding (GO:0005515)

GO Cellular Component (9): postsynaptic density (GO:0014069), AMPA glutamate receptor complex (GO:0032281), dendritic spine membrane (GO:0032591), postsynaptic membrane (GO:0045211), postsynaptic density membrane (GO:0098839), asymmetric, glutamatergic, excitatory synapse (GO:0098985), membrane (GO:0016020), synapse (GO:0045202), glutamatergic synapse (GO:0098978)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
postsynaptic membrane	2
postsynaptic specialization membrane	2
asymmetric synapse	2
synaptic membrane	2
developmental process involved in reproduction	1
male gamete generation	1
cell surface receptor signaling pathway	1
regulation of neuronal synaptic plasticity	1
negative regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
receptor localization to synapse	1
regulation of postsynaptic membrane neurotransmitter receptor levels	1
neurotransmitter receptor diffusion trapping	1
chemical synaptic transmission	1
excitatory postsynaptic potential	1
AMPA glutamate receptor clustering	1
regulation of glutamate receptor clustering	1
protein domain specific binding	1
glutamate receptor binding	1
binding	1
postsynaptic specialization	1
ionotropic glutamate receptor complex	1
neuron projection membrane	1
dendrite membrane	1
dendritic spine	1
postsynapse	1
postsynaptic density	1
excitatory synapse	1
glutamatergic synapse	1
cellular anatomical structure	1
cell junction	1
synapse	1

Protein interactions and networks

STRING

974 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHISA6	GSG1L2	A8MUP6	569
SHISA6	PRSS56	P0CW18	555
SHISA6	DLG4	P78352	555
SHISA6	CNIH1	O95406	451
SHISA6	ZMAT4	Q9H898	445
SHISA6	CNIH2	Q6PI25	444
SHISA6	TXLNB	Q8N3L3	434
SHISA6	CACNG8	Q8WXS5	433
SHISA6	TRPV2	Q9Y5S1	433
SHISA6	GSG1L	Q6UXU4	433
SHISA6	CNIH4	Q9P003	419
SHISA6	CDRT15	Q96T59	418
SHISA6	RDH5	Q92781	402
SHISA6	GJD2	Q9UKL4	390
SHISA6	DNAH9	Q9NYC9	371

IntAct

96 interactions, top by confidence:

A	B	Type	Score
CCDC57	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
TLE5	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
CARD9	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
LMO3	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
CIAO1	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
ARMC7	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
CDKN1A	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
EXOSC5	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
UBASH3A	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
KIF9	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
TTC19	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
PLEKHG4	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
NEDD4	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
KRT31	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
GOLGA2	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
HSF2BP	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
TRIP6	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
SHISA6	KIFC3	psi-mi:“MI:0915”(physical association)	0.560
OIP5	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
SHISA6	PFDN5	psi-mi:“MI:0915”(physical association)	0.560
CTBP2	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
BAG3	SHISA6	psi-mi:“MI:0915”(physical association)	0.560
SHISA6	FBLIM1	psi-mi:“MI:0915”(physical association)	0.560
SHISA6	KRTAP3-3	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (39): SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid), SHISA6 (Two-hybrid)

ESM2 similar proteins: A1XQX3, A1XQY0, A1XQY3, A2ALI5, A6QLD2, B5X216, D0PRN4, E9PUN2, O35181, O75151, O94933, O94991, P0C7U0, P15379, P23470, P49415, P56975, P58401, P80560, Q05909, Q3SXY7, Q3UH99, Q3V1G4, Q4W8E7, Q58EG3, Q5EGE1, Q5R3F8, Q5R5B8, Q63376, Q63475, Q68BL8, Q68FM6, Q6QD51, Q6ZSJ9, Q76KF0, Q80Z10, Q810B7, Q810B9, Q8AXP2, Q8C8T7

Diamond homologs: A6NL88, A7MC48, B3DHW5, B4DS77, B8ZZ34, J3QNX5, Q3UH99, Q6ZSJ9, Q8C3Q5, Q9CZN4, A0PJX4, A2RV66, A6QPA0, Q3UPR0, Q5BLC7, Q6UWI4, Q7T0Z7, Q8QZV2, Q8CA71, Q96DD7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	110
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2905 predictions. Top by Δscore:

Variant	Effect	Δscore
17:11249994:GCCT:G	donor_gain	1.0000
17:11379508:GG:G	donor_gain	1.0000
17:11379509:GG:G	donor_gain	1.0000
17:11467635:A:T	donor_gain	1.0000
17:11555737:CAG:C	acceptor_gain	1.0000
17:11555738:A:AG	acceptor_gain	1.0000
17:11555738:AGA:A	acceptor_gain	1.0000
17:11555739:G:C	acceptor_gain	1.0000
17:11555739:G:GA	acceptor_gain	1.0000
17:11555739:G:T	acceptor_loss	1.0000
17:11555739:GA:G	acceptor_gain	1.0000
17:11555739:GAGA:G	acceptor_gain	1.0000
17:11555739:GAGAA:G	acceptor_gain	1.0000
17:11555888:GC:G	donor_gain	1.0000
17:11555888:GCTAA:G	donor_gain	1.0000
17:11555889:C:G	donor_gain	1.0000
17:11555889:CTAA:C	donor_gain	1.0000
17:11555890:TAAGT:T	donor_loss	1.0000
17:11555893:G:C	donor_loss	1.0000
17:11555893:G:GG	donor_gain	1.0000
17:11555894:T:G	donor_loss	1.0000
17:11557752:A:AG	acceptor_gain	1.0000
17:11557752:AGCC:A	acceptor_gain	1.0000
17:11557753:G:GG	acceptor_gain	1.0000
17:11557753:GCC:G	acceptor_gain	1.0000
17:11557753:GCCG:G	acceptor_gain	1.0000
17:11558290:G:GT	donor_gain	1.0000
17:11242058:CAGGT:C	donor_loss	0.9900
17:11242059:AGGTG:A	donor_loss	0.9900
17:11242061:G:GA	donor_loss	0.9900

AlphaMissense

3551 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:11241702:T:A	C94S	1.000
17:11241702:T:C	C94R	1.000
17:11241703:G:A	C94Y	1.000
17:11241703:G:C	C94S	1.000
17:11241703:G:T	C94F	1.000
17:11241704:C:G	C94W	1.000
17:11241708:G:C	G96R	1.000
17:11241708:G:T	G96C	1.000
17:11241711:T:C	Y97H	1.000
17:11241711:T:G	Y97D	1.000
17:11241712:A:G	Y97C	1.000
17:11241714:T:G	Y98D	1.000
17:11241717:G:A	D99N	1.000
17:11241717:G:C	D99H	1.000
17:11241717:G:T	D99Y	1.000
17:11241718:A:C	D99A	1.000
17:11241718:A:G	D99G	1.000
17:11241718:A:T	D99V	1.000
17:11241719:C:A	D99E	1.000
17:11241719:C:G	D99E	1.000
17:11241726:G:T	G102C	1.000
17:11241727:G:A	G102D	1.000
17:11241727:G:T	G102V	1.000
17:11241735:G:C	D105H	1.000
17:11241736:A:C	D105A	1.000
17:11241736:A:G	D105G	1.000
17:11241736:A:T	D105V	1.000
17:11241744:T:C	F108L	1.000
17:11241745:T:C	F108S	1.000
17:11241745:T:G	F108C	1.000

dbSNP variants (sampled 300 via entrez): RS1000010807 (17:11412654 G>T), RS1000027790 (17:11453217 T>C), RS1000036531 (17:11537923 A>C), RS1000041384 (17:11447898 T>G), RS1000043879 (17:11433315 G>A), RS1000057513 (17:11254657 G>A,T), RS1000058396 (17:11369067 G>A), RS1000059118 (17:11459436 G>C), RS1000076171 (17:11453359 C>G,T), RS1000083735 (17:11335608 C>T), RS1000088665 (17:11536784 C>A), RS1000117816 (17:11465634 G>A), RS1000124605 (17:11521163 C>A,G), RS1000129601 (17:11453035 T>C), RS1000129825 (17:11453575 A>G)

Disease associations

OMIM: gene MIM:617327 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST001762_348	Obesity-related traits	2.000000e-06
GCST001762_442	Obesity-related traits	2.000000e-06
GCST001858_26	Refractive error	7.000000e-11
GCST002286_6	Ischemic stroke	5.000000e-06
GCST002938_40	Copper levels	8.000000e-06
GCST003518_78	Daytime sleep phenotypes	7.000000e-06
GCST003997_26	Myopia	5.000000e-24
GCST005655_2	Seborrheic dermatitis	2.000000e-08
GCST006291_135	Spherical equivalent or myopia (age of diagnosis)	9.000000e-29
GCST007324_26	Adventurousness	6.000000e-10
GCST007559_25	Sleep duration (short sleep)	3.000000e-08
GCST008155_68	Waist-hip ratio	1.000000e-06
GCST008159_75	Waist-to-hip ratio adjusted for BMI	1.000000e-06
GCST010002_120	Refractive error	4.000000e-84

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0004471	insulin sensitivity measurement
EFO:0007828	daytime rest measurement
EFO:0004847	age at onset
EFO:0008579	risk-taking behaviour
EFO:0004343	waist-hip ratio
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
mercuric bromide	affects cotreatment, decreases expression	2
Resveratrol	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Valproic Acid	decreases expression, decreases methylation	2
bisphenol A	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
Fulvestrant	decreases methylation	1
Panobinostat	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Copper	affects cotreatment, decreases expression	1
Lead	affects expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	decreases expression	1
Triclosan	decreases expression	1

Clinical trials (associated diseases)

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