SHISA7

Summary

SHISA7 (shisa family member 7, HGNC:35409) is a protein-coding gene on chromosome 19q13.42, encoding Protein shisa-7 (A6NL88). Transmembrane protein that regulates gamma-aminobutyric acid type A receptor (GABA(A)R) trafficking, channel deactivation kinetics and pharmacology, necessary for fast inhibitory transmission in the brain.

Predicted to enable GABA receptor binding activity and ionotropic glutamate receptor binding activity. Predicted to be involved in several processes, including gamma-aminobutyric acid receptor clustering; positive regulation of long-term synaptic potentiation; and regulation of signaling receptor activity. Predicted to be located in asymmetric, glutamatergic, excitatory synapse. Predicted to be active in glutamatergic synapse; postsynaptic density; and synaptic membrane.

Source: NCBI Gene 729956 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_001145176

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:35409
Approved symbol	SHISA7
Name	shisa family member 7
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000187902
Ensembl biotype	protein_coding
OMIM	617328
Entrez	729956

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000376325, ENST00000416792

RefSeq mRNA: 1 — MANE Select: NM_001145176 NM_001145176

CCDS: CCDS46193

Canonical transcript exons

ENST00000376325 — 4 exons

Exon	Start	End
ENSE00001376018	55428740	55433796
ENSE00001380066	55440611	55440765
ENSE00003537781	55437605	55437754
ENSE00003921060	55442193	55443300

Expression profiles

Bgee: expression breadth broad, 85 present calls, max score 88.07.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.6038 / max 85.7767, expressed in 114 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182812	0.3276	104
182814	0.1745	34
182813	0.0849	17
182807	0.0167	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nucleus accumbens	UBERON:0001882	88.07	gold quality
entorhinal cortex	UBERON:0002728	86.87	gold quality
right frontal lobe	UBERON:0002810	86.67	gold quality
cortical plate	UBERON:0005343	86.39	gold quality
superior frontal gyrus	UBERON:0002661	85.12	gold quality
Ammon’s horn	UBERON:0001954	85.10	gold quality
caudate nucleus	UBERON:0001873	85.05	gold quality
temporal lobe	UBERON:0001871	85.04	gold quality
putamen	UBERON:0001874	85.00	gold quality
amygdala	UBERON:0001876	84.85	gold quality
anterior cingulate cortex	UBERON:0009835	84.52	gold quality
postcentral gyrus	UBERON:0002581	84.37	gold quality
Brodmann (1909) area 9	UBERON:0013540	83.84	gold quality
cerebral cortex	UBERON:0000956	83.17	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.08	gold quality
neocortex	UBERON:0001950	82.87	gold quality
parietal lobe	UBERON:0001872	82.76	gold quality
frontal cortex	UBERON:0001870	82.75	gold quality
forebrain	UBERON:0001890	82.31	gold quality
hypothalamus	UBERON:0001898	81.71	gold quality
medial globus pallidus	UBERON:0002477	81.56	gold quality
primary visual cortex	UBERON:0002436	81.29	gold quality
middle temporal gyrus	UBERON:0002771	81.12	silver quality
left ventricle myocardium	UBERON:0006566	81.07	gold quality
brain	UBERON:0000955	80.95	gold quality
prefrontal cortex	UBERON:0000451	80.75	gold quality
buccal mucosa cell	CL:0002336	80.60	gold quality
cardiac muscle of right atrium	UBERON:0003379	80.58	gold quality
globus pallidus	UBERON:0001875	80.12	gold quality
tendon of biceps brachii	UBERON:0008188	79.25	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.63

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

280 targeting SHISA7, 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-513A-5P	100.00	69.77	2465
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4510	100.00	66.60	2050
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-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-432-3P	100.00	67.86	705
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580

Literature-anchored findings (GeneRIF, showing 1)

• Enhancer Function of MicroRNA-3681 Derived from Long Terminal Repeats Represses the Activity of Variable Number Tandem Repeats in the 3’ UTR of SHISA7. (PMID:32655015)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	shisa7a	ENSDARG00000062462
danio_rerio	shisa7b	ENSDARG00000063144
mus_musculus	Shisa7	ENSMUSG00000053550
rattus_norvegicus	Shisa7	ENSRNOG00000016877

Paralogs (3): SHISA6 (ENSG00000188803), SHISA8 (ENSG00000234965), SHISA9 (ENSG00000237515)

Protein

Protein identifiers

Protein shisa-7 — A6NL88 (reviewed: A6NL88)

Alternative names: Cystine-knot AMPAR modulating protein of 59 kDa, GABA(A) receptor auxiliary subunit Shisa7, Protein shisa-6-like

All UniProt accessions (2): A6NL88, H7C1N4

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane protein that regulates gamma-aminobutyric acid type A receptor (GABA(A)R) trafficking, channel deactivation kinetics and pharmacology, necessary for fast inhibitory transmission in the brain. Enhances the action of benzodiazepine, a primary GABA(A)Rs target drug, in the brain. May affect channel kinetics of AMPA-type glutamate receptors (AMPAR), the brain’s main excitatory neurotransmitter, necessary for synaptic hippocampal plasticity, and memory recall. May regulate the induction and maintenance of long-term potentiation at Schaffer collaterals/CA3-CA1 excitatory synapses.

Subunit / interactions. Interacts with GABA(A)R (GABA type A receptor) subunits GABRA1, GABRA2 and GABRG2; the interaction is direct. Does not interact with GABRB2 and GABRB3 subunits. May interact with AMPAR subunits GRIA1, GRIA2 and GRIA3 and AMPAR auxiliary proteins SHISA6 and SHISA7. May interact (via PDZ-binding motif) with DLG4/PSD-95 (via PDZ domain); the interaction is direct.

Subcellular location. Postsynaptic density membrane.

Domain organisation. The PDZ-binding motif interacts with PDZ-domain of scaffolding protein DLG4. The GRID (GABA(A)R-interacting domain) is critical for its subcellular localization and interaction with GABA(A)R.

Similarity. Belongs to the shisa family.

RefSeq proteins (1): NP_001138648* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026910	Shisa	Family
IPR053891	Shisa_N	Domain

Pfam: PF13908

UniProt features (19 total): compositionally biased region 5, region of interest 4, modified residue 2, glycosylation site 2, topological domain 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-A6NL88-F1	54.54	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 (2): 417, 512

Glycosylation sites (2): 23, 59

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, TGCGCANK_UNKNOWN, GCANCTGNY_MYOD_Q6, AAGCCAT_MIR135A_MIR135B, GOBP_GAMMA_AMINOBUTYRIC_ACID_SIGNALING_PATHWAY, TGACCTY_ERR1_Q2, HATADA_METHYLATED_IN_LUNG_CANCER_DN, GOBP_CELL_CELL_SIGNALING, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_REGULATION_OF_SYNAPTIC_PLASTICITY, MYOD_01, GOBP_REGULATION_OF_CELLULAR_LOCALIZATION, GOBP_POSTSYNAPTIC_MEMBRANE_ORGANIZATION

GO Biological Process (5): gamma-aminobutyric acid signaling pathway (GO:0007214), memory (GO:0007613), gamma-aminobutyric acid receptor clustering (GO:0097112), regulation of GABA-A receptor activity (GO:0106040), positive regulation of long-term synaptic potentiation (GO:1900273)

GO Molecular Function (1): GABA receptor binding (GO:0050811)

GO Cellular Component (8): postsynaptic density (GO:0014069), dendritic spine membrane (GO:0032591), postsynaptic membrane (GO:0045211), postsynaptic density membrane (GO:0098839), plasma membrane (GO:0005886), membrane (GO:0016020), synapse (GO:0045202), postsynaptic specialization membrane (GO:0099634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synaptic membrane	3
postsynaptic specialization	2
postsynaptic membrane	2
cell-cell signaling	1
GABA receptor activity	1
learning or memory	1
postsynaptic membrane organization	1
neurotransmitter-gated ion channel clustering	1
GABA-A receptor activity	1
regulation of signaling receptor activity	1
positive regulation of synaptic transmission	1
long-term synaptic potentiation	1
regulation of long-term synaptic potentiation	1
signaling receptor binding	1
asymmetric synapse	1
neuron projection membrane	1
dendrite membrane	1
dendritic spine	1
postsynapse	1
postsynaptic density	1
postsynaptic specialization membrane	1
membrane	1
cell periphery	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1078 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SHISA7	GSG1L	Q6UXU4	500
SHISA7	BCAS4	Q8TDM0	467
SHISA7	CACNG8	Q8WXS5	461
SHISA7	CLPTM1	O96005	446
SHISA7	LHFPL4	Q7Z7J7	400
SHISA7	CNIH2	Q6PI25	398
SHISA7	CNIH4	Q9P003	364
SHISA7	CNIH1	O95406	356
SHISA7	GPHN	Q9NQX3	348
SHISA7	SYNDIG1	Q9H7V2	347
SHISA7	CACNG2	Q9Y698	329
SHISA7	ZNF300	Q96RE9	325
SHISA7	PGBD4	Q96DM1	321
SHISA7	DLGAP3	O95886	318
SHISA7	TMEM145	Q8NBT3	312

IntAct

0 interactions, top by confidence:

BioGRID (1): SHISA7 (Positive Genetic)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A2R8YCJ5, A2A699, A2AEV7, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NL88, A8MVW0, A9JSM3, B2RU40, B8ZZ34, C9JH25, D4A9R4, J3QNX5, P0CG09, P98077, Q0VD38, Q14761, Q17QH7, Q29RK8, Q2KJ18, Q2M3V2, Q3SX20, Q5BJT1, Q5HZJ5, Q5RKR3, Q5T442, Q64697, Q69YZ2, Q6PB97, Q6PCT2, Q6UXK2, Q6ZMQ8, Q6ZVH7, Q6ZW31, Q80XF7, Q8BLS7

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	57
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

897 predictions. Top by Δscore:

Variant	Effect	Δscore
19:55437760:T:C	acceptor_gain	1.0000
19:55437760:T:TC	acceptor_gain	1.0000
19:55440606:CTCA:C	donor_loss	1.0000
19:55440607:TCA:T	donor_loss	1.0000
19:55440608:CA:C	donor_loss	1.0000
19:55440609:A:AC	donor_gain	1.0000
19:55440609:A:AT	donor_loss	1.0000
19:55440610:C:CC	donor_gain	1.0000
19:55440610:C:CT	donor_loss	1.0000
19:55440761:GAGCT:G	acceptor_gain	1.0000
19:55440764:CT:C	acceptor_gain	1.0000
19:55440765:TC:T	acceptor_loss	1.0000
19:55440766:C:CC	acceptor_gain	1.0000
19:55440767:T:A	acceptor_loss	1.0000
19:55433794:CGG:C	acceptor_gain	0.9900
19:55433797:C:CC	acceptor_gain	0.9900
19:55437599:ACT:A	donor_loss	0.9900
19:55437600:CTC:C	donor_loss	0.9900
19:55437601:TCA:T	donor_loss	0.9900
19:55437602:CAC:C	donor_loss	0.9900
19:55437603:A:AC	donor_gain	0.9900
19:55437603:AC:A	donor_gain	0.9900
19:55437604:C:CC	donor_gain	0.9900
19:55437604:CC:C	donor_gain	0.9900
19:55437604:CCCAG:C	donor_gain	0.9900
19:55437750:CCAGT:C	acceptor_gain	0.9900
19:55437751:CAGT:C	acceptor_gain	0.9900
19:55437751:CAGTC:C	acceptor_gain	0.9900
19:55437753:GT:G	acceptor_gain	0.9900
19:55437754:TCTG:T	acceptor_loss	0.9900

AlphaMissense

3384 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:55442277:G:T	A196D	1.000
19:55442282:G:C	S194R	1.000
19:55442282:G:T	S194R	1.000
19:55442284:T:G	S194R	1.000
19:55442286:A:T	I193N	1.000
19:55442292:C:T	G191E	1.000
19:55442456:C:A	W136C	1.000
19:55442456:C:G	W136C	1.000
19:55442458:A:G	W136R	1.000
19:55442458:A:T	W136R	1.000
19:55442481:C:G	C128S	1.000
19:55442481:C:T	C128Y	1.000
19:55442482:A:T	C128S	1.000
19:55442516:A:C	C116W	1.000
19:55442517:C:A	C116F	1.000
19:55442517:C:G	C116S	1.000
19:55442517:C:T	C116Y	1.000
19:55442518:A:G	C116R	1.000
19:55442518:A:T	C116S	1.000
19:55442519:G:C	C115W	1.000
19:55442520:C:G	C115S	1.000
19:55442520:C:T	C115Y	1.000
19:55442521:A:G	C115R	1.000
19:55442521:A:T	C115S	1.000
19:55442522:G:C	F114L	1.000
19:55442522:G:T	F114L	1.000
19:55442523:A:C	F114C	1.000
19:55442523:A:G	F114S	1.000
19:55442524:A:G	F114L	1.000
19:55442524:A:T	F114I	1.000

dbSNP variants (sampled 300 via entrez): RS1000102308 (19:55444775 T>C), RS1000452962 (19:55444511 A>T), RS1000500289 (19:55432582 T>C), RS1000661259 (19:55440362 C>T), RS1000761622 (19:55432873 G>T), RS1000845653 (19:55436603 C>A), RS1000879639 (19:55437584 G>C,T), RS1001201568 (19:55435632 C>G), RS1001273843 (19:55445130 C>G), RS1001327624 (19:55442885 T>A,C), RS1001476463 (19:55438509 G>A,T), RS1002023473 (19:55441319 G>T), RS1002171138 (19:55433998 C>T), RS1002675205 (19:55430488 T>C), RS1002732681 (19:55441521 C>G)

Disease associations

OMIM: gene MIM:617328 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
abrine	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation	1
Phthalic Acids	increases methylation	1
Smoke	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1
Particulate Matter	increases abundance, increases expression	1

Clinical trials (associated diseases)

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