AQP4

Summary

AQP4 (aquaporin 4, HGNC:637) is a protein-coding gene on chromosome 18q11.2, encoding Aquaporin-4 (P55087). Forms a water-specific channel.

This gene encodes a member of the aquaporin family of intrinsic membrane proteins that function as water-selective channels in the plasma membranes of many cells. This protein is the predominant aquaporin found in brain and has an important role in brain water homeostasis. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. Additional isoforms, resulting from the use of alternative in-frame translation initiation codons, have also been described. Recent studies provided evidence for translational readthrough in this gene, and expression of C-terminally extended isoforms via the use of an alternative in-frame translation termination codon.

Source: NCBI Gene 361 — RefSeq curated summary.

At a glance

• Gene–disease (curated): megalencephalic leukoencephalopathy with subcortical cysts 4, remitting (Moderate, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 60 total — 4 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 17
• Druggable target: yes
• MANE Select transcript: NM_001650

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:637
Approved symbol	AQP4
Name	aquaporin 4
Location	18q11.2
Locus type	gene with protein product
Status	Approved
Aliases	MIWC, AQP-4, hAQP4
Ensembl gene	ENSG00000171885
Ensembl biotype	protein_coding
OMIM	600308
Entrez	361

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 8 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000383168, ENST00000383170, ENST00000440832, ENST00000578776, ENST00000581374, ENST00000583022, ENST00000584088, ENST00000672188, ENST00000672981, ENST00000675739, ENST00000906982

RefSeq mRNA: 7 — MANE Select: NM_001650 NM_001317384, NM_001317387, NM_001364286, NM_001364287, NM_001364289, NM_001650, NM_004028

CCDS: CCDS11889, CCDS58617, CCDS82244, CCDS92445

Canonical transcript exons

ENST00000383168 — 5 exons

Exon	Start	End
ENSE00001836588	26852043	26856489
ENSE00002236389	26865658	26865707
ENSE00003511494	26860772	26860852
ENSE00003563926	26862182	26862596
ENSE00003588899	26861131	26861295

Expression profiles

Bgee: expression breadth ubiquitous, 218 present calls, max score 99.98.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 24.7609 / max 1501.9709, expressed in 162 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171479	10.2464	142
171481	8.7077	125
171482	2.5040	102
171480	1.9836	119
171477	0.3431	80
171476	0.2196	76
171467	0.2118	48
171462	0.1094	36
171468	0.0993	27
171463	0.0872	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	99.98	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.92	gold quality
substantia nigra pars compacta	UBERON:0001965	99.90	gold quality
superior vestibular nucleus	UBERON:0007227	99.84	gold quality
subthalamic nucleus	UBERON:0001906	99.79	gold quality
ventral tegmental area	UBERON:0002691	99.75	gold quality
globus pallidus	UBERON:0001875	99.70	gold quality
medial globus pallidus	UBERON:0002477	99.65	gold quality
inferior vagus X ganglion	UBERON:0005363	99.35	gold quality
lower lobe of lung	UBERON:0008949	99.16	gold quality
corpus callosum	UBERON:0002336	99.02	gold quality
lateral nuclear group of thalamus	UBERON:0002736	98.90	gold quality
nucleus accumbens	UBERON:0001882	98.89	gold quality
entorhinal cortex	UBERON:0002728	98.89	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.84	gold quality
pons	UBERON:0000988	98.82	gold quality
caudate nucleus	UBERON:0001873	98.82	gold quality
biceps brachii	UBERON:0001507	98.76	gold quality
amygdala	UBERON:0001876	98.70	gold quality
temporal lobe	UBERON:0001871	98.58	gold quality
parietal lobe	UBERON:0001872	98.48	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.43	gold quality
postcentral gyrus	UBERON:0002581	98.35	gold quality
putamen	UBERON:0001874	98.24	gold quality
cranial nerve II	UBERON:0000941	98.06	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.87	gold quality
superior frontal gyrus	UBERON:0002661	97.64	gold quality
Ammon’s horn	UBERON:0001954	97.50	gold quality
midbrain	UBERON:0001891	97.48	gold quality
endothelial cell	CL:0000115	97.47	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-MTAB-9435	yes	1223.76
E-MTAB-10662	yes	1093.38
E-HCAD-35	yes	81.06
E-HCAD-25	yes	29.65
E-GEOD-84465	yes	27.82
E-MTAB-7316	yes	23.14
E-HCAD-1	yes	20.83
E-GEOD-130148	yes	12.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, HNF4A, NFAT5

miRNA regulators (miRDB)

209 targeting AQP4, 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-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996

Literature-anchored findings (GeneRIF, showing 40)

• Restricted to astrocytes. Detectable in subpial and subependymal zone in normal condition. More intense in ischemic foci. May reflect participation in development of brain edema in human brains by playing role in water transport. (PMID:12715185)
• AQP4 mRNA failed to localize in parietal cells but was identified in neighboring mucosal cells that were triangular in shape and smaller than parietal cells in size, and in columnar cells at the base of the gastric gland. (PMID:14627352)
• Increased expression. Over-expression occurred on astrocytic processes. Induction of AQP1 and AQP4 on reactive astrocytes in subarachnoid hemorrhage. May be involved in brain edema formation or resolution. (PMID:14753493)
• The expression of AQP4 is affected by nerve supply and is down-regulated in human muscles with neurogenic atrophy. (PMID:15200272)
• aquaporin-4 has species-specific roles in astrocytes and a functional relationship with Connexin43 (PMID:16103109)
• Up-regulation of AQP4 was found in astrocytes in various inflammatory lesions. Distribution of AQP4-positve astrocytes differed according to disease and was’nt related to brain edema. Thus, functions and regulation of AQP4 in human brains are multiple. (PMID:16133546)
• Astrocytic impairment and humoral immunity against AQP4 may be primarily involved in the lesion formation of NEUROMYELITIS OPTICA, contrarely to MULTIPLE SCLEROSIS in which demyelination is the primary pathology. (PMID:16778375)
• These results in human fetal brain lend morphological support to the previous findings that aquaporin-1 and aquaporin-4 play different roles in the regulation of the water homeostasis of the brain. (PMID:16814974)
• The distribution of NMO-characteristic brain lesions corresponds to sites of high AQP4 expression in neuromyelitis optica (PMID:16831965)
• Significant increased expression levels of AQP1 and AQP4 were seen in Creutzfeldt-Jakob disease, but not in advanced Alzheimer’s disease and diffuse Lewy body disease. (PMID:16871401)
• Unexpectedly high AQP4 levels in pilocytic astrocytomas and present AQP4 as tumor progression marker in WHO grade II-IV astrocytomas. (PMID:17335082)
• Only the presence of AQP1, but not AQP4, enhanced cell growth and migration, typical properties of gliomas, while AQP4 enhanced cell adhesion suggesting differential biological roles for AQP1 and AQP4 in glioma cell biology. (PMID:17549682)
• We did not find any variation in exon 4 of the AQP4 gene in our considerable large sample of traumatic brain edema. (PMID:17890008)
• increased AQP-4 expression in sCJD is an early pathologic event and appears to remain until the late disease stage (PMID:17899684)
• upregulated expression of chromosome 21 genes such as S100B and amyloid precursor protein activated the stress response kinase pathways, and furthermore, could be linked to upregulation of the water channel aquaporin 4 in Down syndrome neural progenitors (PMID:17984171)
• AQP4-mediated maternal-fetal fluid exchange could play an important role in the control of ion homeostasis and water balance in the human placenta throughout pregnancy (PMID:18019416)
• Review highlights an understanding of the major role of aquaporin-4 in maintenance of the microenvironment of neurons, axons, and oligodendrocytes and its importance as a therapeutic target in neurologic disease. (PMID:18071147)
• Upregulation of APQ4 by tumor cells and reactive astroglia were major factors of cerebral edema (PMID:18095136)
• AQP4 is not expressed in human airway epithelial cells from the A549 adeoncarcinoma cell line. (PMID:18280225)
• genetic variation in AQP4 might contribute to brain edema formation after middle cerebral artery occlusion (PMID:18309154)
• Our study shows that AQP4 downregulation can occur in muscular dystrophies with either normal or disrupted expression of dystrophin-associated proteins, and that this might be associated with upregulation of AQP1. (PMID:18392839)
• These data suggest that changes are apparent in markers for abnormal glial-neuronal communication (connexin 43 and aquaporin 4) in brains of subjects with autism. (PMID:18435417)
• Presence of anti-AQP4 antibodies correlates with clinical severity and poor prognosis in opticospinal multiple sclerosis. (PMID:18437047)
• Elevated anti-AQP4 antibody titers in serum were found in 15 (71%) of 21 patients with neuromyelitis optica, 4.3% of 46 patients with multiple sclerosis, none of 51 normal controls, and 2.6% of 115 patients with other neurological diseases. (PMID:18462810)
• Aquaporin-4-specific IgG in some cases of NMO may reflect a paraneoplastic immune response. The clinical utility of this autoantibody as a cancer marker warrants prospective investigation. (PMID:18474738)
• Changes in AQP4 expression & blood-brain barrier integrity, both of which can be regulated by CNS inflammation, contribute to inductive events for anti-AQP4-specific immune response in neuromyelitis optica. Review. (PMID:18510734)
• 24 variants in AQP4 including four novel nsSNPs (I128T, D184E, I205L and M224T) were identified. (PMID:18511455)
• may be involved in the pathogenesis of Neuromyelitis optica. (PMID:18516975)
• AQP4 expression was analyzed in muscle biopsies from patients affected by Limb Girdle Muscular Dystrophies. (PMID:18641458)
• This study was designed to analyze changes in the expression of AQP4 following elevation of intraocular pressure (IOP) and after intravitreal endothelin-1 injection and the potential involvement of the ubiquitin-dependent proteasome. (PMID:18836575)
• These observations indicate that the C-terminal domain of AQP4 is constitutively phosphorylated at least in part by protein kinase CK2 and it is required for Golgi transition. (PMID:18854171)
• Secondary edema and brain damage may correlate with the expression of the AQP-4 mRNA in the peri-hematoma brain edema area. (PMID:19000426)
• hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse in multiple sclerosis (PMID:19028829)
• We measured the expression and localization of AQP4 in 60 gastric epithelial tumor cases and 10 normal tissue cases. AQP4 protein and mRNA expression level in gastric cancer tissue were significantly lower than those in normal gastric tissue. (PMID:19112001)
• the emergence of anti-AQP4 antibody is reinforced by the presence of the HLA-DPB1*0501 allele in Japanese. (PMID:19140826)
• Aquaporin 4 overexpression can lead to abnormal water transport and edema formation in meningiomas. (PMID:19153045)
• We describe a case of narcolepsy as an initial manifestation of neuromyelitis optica with anti-aquaporin-4 antibody. (PMID:19266146)
• Role for AQP4 in fluid regulation in inner retina. AQP4 channels are likely a conduit for facilitating fluid homeostasis in inner retina during light activation, are likely to play a consequent role in the regulation of ocular volume and growth. [Review] (PMID:19366470)
• The 1.8-A crystal structure of AQ4 reveals the molecular basis for the water selectivity of the channel. (PMID:19383790)
• Accessory isoforms AQP4a and AQP4e, while not being able to form square arrays alone, are able to interact with functional isoform AQP4c and be incorporated into higher-order structures. (PMID:19445480)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	aqp4	ENSDARG00000010565
mus_musculus	Aqp4	ENSMUSG00000024411
rattus_norvegicus	Aqp4	ENSRNOG00000016043
drosophila_melanogaster	Eglp1	FBGN0034882
drosophila_melanogaster	Eglp2	FBGN0034883
drosophila_melanogaster	Eglp3	FBGN0034884
drosophila_melanogaster	Eglp4	FBGN0034885

Paralogs (11): AQP6 (ENSG00000086159), AQP8 (ENSG00000103375), AQP9 (ENSG00000103569), MIP (ENSG00000135517), AQP10 (ENSG00000143595), AQP5 (ENSG00000161798), AQP7 (ENSG00000165269), AQP3 (ENSG00000165272), AQP2 (ENSG00000167580), AQP1 (ENSG00000240583), AQP7B (ENSG00000259916)

Protein

Protein identifiers

Aquaporin-4 — P55087 (reviewed: P55087)

Alternative names: Mercurial-insensitive water channel, WCH4

All UniProt accessions (6): P55087, A0A5F9ZHR4, F1DSG4, H0Y3H5, J3KRM4, V9PBN7

UniProt curated annotations — full annotation on UniProt →

Function. Forms a water-specific channel. Plays an important role in brain water homeostasis. It is involved in glymphatic solute transport and is required for a normal rate of water exchange across the blood brain interface. Required for normal levels of cerebrospinal fluid influx into the brain cortex and parenchyma along paravascular spaces that surround penetrating arteries, and for normal drainage of interstitial fluid along paravenous drainage pathways. Thereby, it is required for normal clearance of solutes from the brain interstitial fluid, including soluble beta-amyloid peptides derived from APP. Plays a redundant role in urinary water homeostasis and urinary concentrating ability.

Subunit / interactions. Homotetramer. The tetramers can form oligomeric arrays in membranes. The size of the oligomers differs between tissues and is smaller in skeletal muscle than in brain. Interaction between AQP4 oligomeric arrays in close-by cells can contribute to cell-cell adhesion. Part of a complex containing MLC1, TRPV4, HEPACAM and ATP1B1.

Subcellular location. Cell membrane. Basolateral cell membrane. Endosome membrane. Sarcolemma. Cell projection.

Tissue specificity. Detected in skeletal muscle. Detected in stomach, along the glandular base region of the fundic gland (at protein level). Detected in brain, lung and skeletal muscle, and at much lower levels in heart and ovary.

Post-translational modifications. Phosphorylation by PKC at Ser-180 reduces conductance by 50%. Phosphorylation by PKG at Ser-111 in response to glutamate increases conductance by 40%. Isoform 2: Palmitoylated on its N-terminal region. Isoform 1: Not palmitoylated.

Disease relevance. Megalencephalic leukoencephalopathy with subcortical cysts 4, remitting (MLC4) [MIM:620448] An autosomal recessive disorder characterized by macrocephaly apparent in infancy, developmental delay, delayed walking, variable cognitive decline, behavioral abnormalities, and early-onset seizures. Brain imaging shows swelling of the cerebral white matter and subcortical cysts in the anterior temporal region. The severity of neurologic dysfunction and brain abnormalities tends to improve with time, indicating a remitting disease course. The disease may be caused by variants affecting the gene represented in this entry.

Domain organisation. Aquaporins contain two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA).

Similarity. Belongs to the MIP/aquaporin (TC 1.A.8) family.

Isoforms (2)

UniProt ID	Names	Canonical?
P55087-1	2, AQP4-M1	yes
P55087-2	1, AQP4-M23

RefSeq proteins (7): NP_001304313, NP_001304316, NP_001351215, NP_001351216, NP_001351218, NP_001641, NP_004019 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000425	MIP	Family
IPR022357	MIP_CS	Conserved_site
IPR023271	Aquaporin-like	Homologous_superfamily
IPR034294	Aquaporin_transptr	Family

Pfam: PF00230

Catalyzed reactions (Rhea), 1 shown:

• H2O(in) = H2O(out) (RHEA:29667)

UniProt features (47 total): topological domain 9, helix 9, transmembrane region 6, modified residue 6, sequence conflict 3, turn 3, intramembrane region 2, short sequence motif 2, lipid moiety-binding region 2, glycosylation site 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
3GD8	X-RAY DIFFRACTION	1.8
8V8S	ELECTRON MICROSCOPY	2.2
8V91	ELECTRON MICROSCOPY	2.6
8V9D	ELECTRON MICROSCOPY	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55087-F1	80.50	0.62

Antibody-complex structures (SAbDab): 2 — 8V91, 8V9D

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 (8): 111, 180, 276, 285, 289, 321, 13, 17

Glycosylation sites (2): 153, 206

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-432040	Vasopressin regulates renal water homeostasis via Aquaporins
R-HSA-432047	Passive transport by Aquaporins
R-HSA-382551	Transport of small molecules
R-HSA-445717	Aquaporin-mediated transport

MSigDB gene sets: 254 (showing top): MODULE_416, ACTACCT_MIR196A_MIR196B, HOFFMANN_SMALL_PRE_BII_TO_IMMATURE_B_LYMPHOCYTE_DN, GOBP_PROTEIN_HOMOTETRAMERIZATION, GOBP_RESPONSE_TO_PEPTIDE, GOCC_CELL_SURFACE, GGGTGGRR_PAX4_03, MODULE_66, CTAGGAA_MIR384, GOBP_WATER_TRANSPORT, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE, CAGCAGG_MIR370, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, GOBP_CILIUM_MOVEMENT

GO Biological Process (8): renal water homeostasis (GO:0003091), water transport (GO:0006833), intracellular water homeostasis (GO:0009992), multicellular organismal-level water homeostasis (GO:0050891), protein homotetramerization (GO:0051289), cellular response to type II interferon (GO:0071346), cerebrospinal fluid circulation (GO:0090660), transmembrane transport (GO:0055085)

GO Molecular Function (4): water channel activity (GO:0015250), identical protein binding (GO:0042802), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (11): extracellular region (GO:0005576), cytoplasm (GO:0005737), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), endosome membrane (GO:0010008), basolateral plasma membrane (GO:0016323), sarcolemma (GO:0042383), astrocyte end-foot (GO:0097450), endosome (GO:0005768), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aquaporin-mediated transport	2
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
plasma membrane	2
renal system process	1
multicellular organismal-level water homeostasis	1
fluid transport	1
cell volume homeostasis	1
intracellular chemical homeostasis	1
regulation of body fluid levels	1
multicellular organismal-level chemical homeostasis	1
protein homooligomerization	1
protein tetramerization	1
response to type II interferon	1
cellular response to cytokine stimulus	1
epithelial cilium movement involved in extracellular fluid movement	1
nervous system process	1
transport	1
cellular process	1
water transmembrane transporter activity	1
channel activity	1
protein binding	1
binding	1
passive transmembrane transporter activity	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell surface	1
side of membrane	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
basal plasma membrane	1
plasma membrane region	1
astrocyte projection	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

19 interactions, top by confidence:

A	B	Type	Score
WLS	AQP4	psi-mi:“MI:0915”(physical association)	0.620
AQP4	CREB3	psi-mi:“MI:0915”(physical association)	0.560
AQP4	HPCAL4	psi-mi:“MI:0915”(physical association)	0.560
GJA8	AQP4	psi-mi:“MI:0915”(physical association)	0.560
WLS	AQP4	psi-mi:“MI:0915”(physical association)	0.370
	AQP4	psi-mi:“MI:0914”(association)	0.350
PRNP	CARNS1	psi-mi:“MI:0914”(association)	0.350
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
ITM2B	ILVBL	psi-mi:“MI:0914”(association)	0.350
AQP4	HPCAL4	psi-mi:“MI:0915”(physical association)	0.000
AQP4	GJA8	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (8): CREB3 (Two-hybrid), AQP4 (Two-hybrid), AQP4 (Two-hybrid), AQP4 (Affinity Capture-MS), AQP4 (Two-hybrid), AQP4 (Reconstituted Complex), AQP4 (Affinity Capture-MS), AQP4 (Affinity Capture-Western)

ESM2 similar proteins: A2IBY8, A4L9J0, A8W649, A9Y006, G5CTG2, G5CTG4, O43315, O62735, O77750, P06624, P09011, P29972, P29975, P30301, P34080, P41181, P47862, P47863, P47864, P47865, P50501, P51180, P55064, P55087, P55088, P56401, P56402, P56627, P79099, Q02013, Q06019, Q08DE6, Q13520, Q23808, Q5I4F9, Q5R819, Q6J8I9, Q6PQZ1, Q6RZ07, Q866S3

Diamond homologs: A0A384J409, A0A384J441, A0A384J983, A0A384JGJ4, A0A384JL97, A0A384JP03, A2IBY8, A4L9J0, A6ZX66, A7A0K7, A8W649, B0DMR6, B3LTC4, C7GNE2, C8ZCS2, C8ZJM1, G5CTG2, I1Z8E5, I3W9F6, O22588, O62735, O64964, O77750, O82316, O82598, P06624, P09011, P0CD89, P0CD91, P0CD92, P0CD98, P0DO54, P21653, P23958, P24422, P25818, P26587, P28238, P29972, P29975

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
DGC	“up-regulates quantity”	AQP4	binding
CSNK2A1	“down-regulates activity”	AQP4	phosphorylation
CSNK2A2	“down-regulates activity”	AQP4	phosphorylation
PKC	“down-regulates activity”	AQP4	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	1
Uncertain significance	39
Likely benign	6
Benign	5

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
2573132	NM_001650.7(AQP4):c.643G>A (p.Ala215Thr)	Pathogenic
3391936	GRCh37/hg19 18q11.2-12.1(chr18:21553578-32172480)x1	Pathogenic
815998	GRCh37/hg19 18q11.2-12.2(chr18:22868759-34335753)x1	Pathogenic
983154	GRCh37/hg19 18q11.2-12.2(chr18:23971647-33737300)x1	Pathogenic
446492	NM_001650.7(AQP4):c.332G>C (p.Ser111Thr)	Likely pathogenic

SpliceAI

1182 predictions. Top by Δscore:

Variant	Effect	Δscore
18:26860735:A:C	donor_gain	1.0000
18:26861129:A:AC	donor_gain	1.0000
18:26861130:C:CC	donor_gain	1.0000
18:26861130:CTG:C	donor_gain	1.0000
18:26862192:C:CA	donor_gain	1.0000
18:26862236:T:A	donor_gain	1.0000
18:26861122:GAAAC:G	donor_loss	0.9900
18:26861123:AAAC:A	donor_loss	0.9900
18:26861124:AACT:A	donor_loss	0.9900
18:26861125:ACTTA:A	donor_loss	0.9900
18:26861126:CTTA:C	donor_loss	0.9900
18:26861127:TT:T	donor_loss	0.9900
18:26861128:TACTG:T	donor_loss	0.9900
18:26861129:A:T	donor_loss	0.9900
18:26861129:ACTG:A	donor_gain	0.9900
18:26861130:C:T	donor_loss	0.9900
18:26861130:CT:C	donor_gain	0.9900
18:26861130:CTGC:C	donor_gain	0.9900
18:26862205:CCACA:C	donor_gain	0.9900
18:26862209:A:AC	donor_gain	0.9900
18:26862210:C:CC	donor_gain	0.9900
18:26862286:A:AC	donor_gain	0.9900
18:26862287:C:CC	donor_gain	0.9900
18:26862304:T:TA	donor_gain	0.9900
18:26860791:C:A	donor_gain	0.9800
18:26861130:CTGCA:C	donor_gain	0.9800
18:26861293:AACC:A	acceptor_loss	0.9800
18:26861295:CCTAG:C	acceptor_loss	0.9800
18:26861296:C:T	acceptor_loss	0.9800
18:26861297:T:C	acceptor_loss	0.9800

AlphaMissense

2112 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:26860826:A:C	N213K	1.000
18:26860826:A:T	N213K	1.000
18:26861145:C:G	G200R	0.999
18:26861145:C:T	G200R	0.999
18:26861162:C:T	G194E	0.999
18:26861163:C:G	G194R	0.999
18:26861163:C:T	G194R	0.999
18:26862338:G:C	N97K	0.999
18:26862338:G:T	N97K	0.999
18:26862389:G:C	S80R	0.999
18:26862389:G:T	S80R	0.999
18:26862391:T:G	S80R	0.999
18:26862398:A:C	F77L	0.999
18:26862398:A:T	F77L	0.999
18:26862400:A:G	F77L	0.999
18:26862473:G:C	S52R	0.999
18:26862473:G:T	S52R	0.999
18:26862475:T:G	S52R	0.999
18:26856464:C:T	G240E	0.998
18:26856477:C:G	G236R	0.998
18:26856477:C:T	G236R	0.998
18:26856483:A:G	W234R	0.998
18:26856483:A:T	W234R	0.998
18:26860828:T:C	N213D	0.998
18:26860832:G:C	S211R	0.998
18:26860832:G:T	S211R	0.998
18:26860834:T:G	S211R	0.998
18:26861132:G:T	A204E	0.998
18:26861153:A:T	V197D	0.998
18:26861216:G:T	A176D	0.998

dbSNP variants (sampled 300 via entrez): RS1000020578 (18:26859911 C>T), RS1000281068 (18:26865893 A>C,G), RS1000294987 (18:26860237 G>A), RS1000387935 (18:26860478 C>T), RS1000512151 (18:26854190 G>C), RS1000523032 (18:26860909 A>G), RS1000775837 (18:26866939 T>C), RS1001028442 (18:26854534 A>G), RS1001200154 (18:26860273 A>G), RS1001254881 (18:26853340 G>A), RS1001463702 (18:26862513 G>A), RS1001810146 (18:26857460 G>A,T), RS1001846508 (18:26859915 C>T), RS1002008942 (18:26864963 C>T), RS1002015363 (18:26853789 G>A)

Disease associations

OMIM: gene MIM:600308 | disease phenotypes: MIM:620448

GenCC curated gene-disease

Disease	Classification	Inheritance
megalencephalic leukoencephalopathy with subcortical cysts 4, remitting	Moderate	Autosomal recessive
intellectual disability	Limited	Autosomal dominant
neuromyelitis optica	Limited	Unknown

Mondo (3): megalencephalic leukoencephalopathy with subcortical cysts 4, remitting (MONDO:0957534), intellectual disability (MONDO:0001071), neuromyelitis optica (MONDO:0019100)

Orphanet (1): NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

17 total (17 of 17 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000256	Macrocephaly
HP:0000752	Hyperactivity
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002015	Dysphagia
HP:0002063	Rigidity
HP:0002066	Gait ataxia
HP:0002133	Status epilepticus
HP:0002312	Clumsiness
HP:0003593	Infantile onset
HP:0100710	Impulsivity
HP:6000461	Cerebral subcortical cyst

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST005984_66	Glomerular filtration rate	6.000000e-09
GCST005985_17	Creatinine levels	3.000000e-09
GCST007344_36	Estimated glomerular filtration rate	6.000000e-07
GCST007344_7	Estimated glomerular filtration rate	2.000000e-11
GCST008058_244	Estimated glomerular filtration rate	2.000000e-13
GCST008060_30	Estimated glomerular filtration rate	5.000000e-07
GCST008062_89	Blood urea nitrogen levels	5.000000e-11
GCST008064_43	Chronic kidney disease	2.000000e-10
GCST009391_542	Metabolite levels	4.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010531	S-adenosylhomocysteine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009471	Neuromyelitis Optica	C10.114.375.600.500; C10.114.375.800; C10.292.700.550.500; C10.314.350.600.500; C10.314.350.800; C11.640.576.695; C20.111.258.250.550.500; C20.111.258.250.775

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5964 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Aquaporins

ChEMBL bioactivities

1 potent at pChembl≥5 of 1 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.52	IC50	3000	nM	CHEMBL500566

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Valproic Acid	increases expression, increases methylation	2
lasiocarpine	decreases expression	1
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	1
palmidrol	affects expression	1
trichostatin A	increases expression	1
ethylene dichloride	increases expression	1
ferric citrate	decreases expression	1
3,4,3’,4’-tetrachlorobiphenyl	affects expression	1
CGP 52608	affects binding, increases reaction	1
bisphenol S	decreases methylation	1
Olanzapine	affects response to substance, increases response to substance	1
Arsenic Trioxide	increases expression	1
Ammonia	decreases expression, decreases reaction	1
Cannabidiol	affects expression	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Deoxycholic Acid	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, increases expression	1
Glycocholic Acid	affects cotreatment, increases expression	1
Glycodeoxycholic Acid	affects cotreatment, increases expression	1
Gold	affects binding, decreases expression	1
Lead	affects expression	1
N-Nitrosopyrrolidine	decreases expression	1
Ozone	increases expression	1
Polyethyleneimine	affects binding, decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4422156	Binding	Inhibition of AQP4 (unknown origin) expressed in CHO cells assessed as reduction in aquaporin-mediated cell Volume shrinkage at 10 uM by light scattering based assay	Novel prodrug salts

Cellosaurus cell lines

6 cell lines: 3 spontaneously immortalized cell line, 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A6YR	CHO hAQP4-M1	Spontaneously immortalized cell line	Female
CVCL_A6YS	CHO hAQP4-M1/M23	Spontaneously immortalized cell line	Female
CVCL_A6YT	CHO hAQP4-M23	Spontaneously immortalized cell line	Female
CVCL_B8BC	Abcam HCT 116 AQP4 KO	Cancer cell line	Male
CVCL_B8SG	Abcam MCF-7 AQP4 KO	Cancer cell line	Female
CVCL_B9DF	Abcam A-549 AQP4 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00304291	PHASE4	COMPLETED	A Pilot Study of Mitoxantrone for the Treatment of Recurrent Neuromyelitis Optica (Devic’s Disease)
NCT02021825	PHASE4	UNKNOWN	Efficacy and Safety of Mitoxantrone in Patients With Refractory Neuromyelitis Optica and Spectrum Disorders
NCT02809079	PHASE4	UNKNOWN	Mycophenolate Mofetil Treatment With Neuromyelitis Optica Spectrum Disorders in Chinese Patients
NCT04256252	PHASE4	COMPLETED	Rituximab at Low dosE for neuromyelitiS optiCa spectrUm disordEr (RESCUE)
NCT05269667	PHASE4	TERMINATED	A Study In Neuromyelitis Optica Spectrum Disorder (NMOSD) With Satralizumab As An Intervention
NCT06180278	PHASE4	ACTIVE_NOT_RECRUITING	Long-term, Open-label, Safety Study of Inebilizumab in Neuromyelitis Optica Spectrum Disorder (NMOSD)
NCT06212245	PHASE4	UNKNOWN	A Clinical Research Study of Inebilizumab in Neuromyelitis Optica Spectrum Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT01892345	PHASE3	TERMINATED	A Randomized Controlled Trial of Eculizumab in AQP4 Antibody-positive Participants With NMO (PREVENT Study)
NCT02003144	PHASE3	COMPLETED	An Open Label Extension Trial of Eculizumab in Relapsing NMO Patients
NCT02028884	PHASE3	COMPLETED	Efficacy and Safety Study of Satralizumab (SA237) as Add-on Therapy to Treat Participants With Neuromyelitis Optica (NMO) and NMO Spectrum Disorder (NMOSD)
NCT02073279	PHASE3	COMPLETED	Efficacy and Safety Study of Satralizumab (SA237) as Monotherapy to Treat Participants With Neuromyelitis Optica (NMO) and Neuromyelitis Optica Spectrum Disorder (NMOSD)
NCT02398994	PHASE3	TERMINATED	A Multicentre randomiSed Controlled TRial of IntraVEnous Immunoglobulin Versus Standard Therapy for Transverse Myelitis
NCT03330418	PHASE3	TERMINATED	A Phase III Study of TACI-antibody Fusion Protein Injection (RC18) in Subjects With Neuromyelitis Optica Spectrum Disorders
NCT04201262	PHASE3	COMPLETED	An Efficacy and Safety Study of Ravulizumab in Adult Participants With NMOSD
NCT04660539	PHASE3	COMPLETED	A Study to Evaluate the Safety and Efficacy of Satralizumab in Participants With Neuromyelitis Optica Spectrum Disorder (NMOSD)
NCT05199688	PHASE3	RECRUITING	A Study To Evaluate Pharmacokinetics, Efficacy, Safety, Tolerability, And Pharmacodynamics Of Satralizumab In Pediatric Patients With Aquaporin-4 Antibody Positive Neuromyelitis Optica Spectrum Disorder (NMOSD)
NCT05314010	PHASE3	ACTIVE_NOT_RECRUITING	A Study of MIL62 in Patients With Neuromyelitis Optica Spectrum Disorder (NMOSD)
NCT05730699	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy and Safety of Divozilimab in Patients With Neuromyelitis Optica Spectrum Disorders (AQUARELLE)
NCT06724809	PHASE3	ACTIVE_NOT_RECRUITING	Efficacy, Safety, PK, PD, and ADA of Eculizumab in Chinese Adults With NMOSD
NCT07132398	PHASE3	NOT_YET_RECRUITING	Slow vs. Rapid Glucocorticoids Tapering With Inebilizumab in NMOSD
NCT07557420	PHASE3	NOT_YET_RECRUITING	Efficacy, Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity Study of Ravulizumab in Chinese Adults With Neuromyelitis Optica Spectrum Disorder (NMOSD)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00716066	PHASE2	ACTIVE_NOT_RECRUITING	Autologous Stem Cell Transplant for Neurologic Autoimmune Diseases
NCT01845584	PHASE2	COMPLETED	Phase II Clinical Trial of NPB-01 in Patients With Anti-aquaporin 4 Antibody Positive Neuromyelitis Optica Spectrum Disorder Not Provided Adequate Effect of Therapy to Steroids Plus Therapy.
NCT02166346	PHASE2	COMPLETED	Safety and Efficacy of Sustained Release Dalfampridine in Transverse Myelitis (Re-Launch)
NCT02249676	PHASE2	COMPLETED	Autologous Mesenchymal Stem Cells for the Treatment of Neuromyelitis Optica Spectrum Disorders
NCT02893111	PHASE2	COMPLETED	Efficacy and Safety of Bortezomib as add-on Treatment in Relapsing Neuromyelitis Optica Spectrum Disorder
NCT04064944	PHASE2	UNKNOWN	Comparison of the Efficacy and Safety of Immunoadsorption and Plasma Exchange for Acute Attack of Refractory Neuromyelitis Optica Spectrum Disorders
NCT04614454	PHASE2	COMPLETED	High Frequency Impulse Therapy for Neuropathic Pain in NMOSD
NCT04670770	PHASE2	COMPLETED	An Open Label Study of the Effects of SHR1459 in NMOSDs Patients
NCT05356858	PHASE2	TERMINATED	An Open Label Study of the Effects and Safety of Zanubrutinib in NMOSDs Adult Patients
NCT05549258	PHASE2	RECRUITING	Study of Inebilizumab in Pediatric Subjects With Neuromyelitis Optica Spectrum Disorder