SLC4A11

Summary

SLC4A11 (solute carrier family 4 member 11, HGNC:16438) is a protein-coding gene on chromosome 20p13, encoding Solute carrier family 4 member 11 (Q8NBS3). Multifunctional transporter with an impact in cell morphology and differentiation.

This gene encodes a voltage-regulated, electrogenic sodium-coupled borate cotransporter that is essential for borate homeostasis, cell growth and cell proliferation. Mutations in this gene have been associated with a number of endothelial corneal dystrophies including recessive corneal endothelial dystrophy 2, corneal dystrophy and perceptive deafness, and Fuchs endothelial corneal dystrophy. Multiple transcript variants encoding different isoforms have been described.

Source: NCBI Gene 83959 — RefSeq curated summary.

At a glance

• Gene–disease (curated): corneal dystrophy-perceptive deafness syndrome (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 7
• Clinical variants (ClinVar): 1,294 total — 81 pathogenic, 75 likely-pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_001174089

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16438
Approved symbol	SLC4A11
Name	solute carrier family 4 member 11
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	dJ794I6.2, BTR1, NaBC1, FECD4
Ensembl gene	ENSG00000088836
Ensembl biotype	protein_coding
OMIM	610206
Entrez	83959

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 14 protein_coding, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000380056, ENST00000380059, ENST00000437836, ENST00000470631, ENST00000474451, ENST00000488544, ENST00000642402, ENST00000644011, ENST00000644692, ENST00000644862, ENST00000645524, ENST00000647296, ENST00000876657, ENST00000876658, ENST00000876659, ENST00000925550, ENST00000925551, ENST00000925552

RefSeq mRNA: 8 — MANE Select: NM_001174089 NM_001174089, NM_001174090, NM_001363745, NM_001400277, NM_001400278, NM_001400279, NM_001400280, NM_032034

CCDS: CCDS13052, CCDS54445, CCDS54446, CCDS86932

Canonical transcript exons

ENST00000642402 — 20 exons

Exon	Start	End
ENSE00001799962	3239095	3239190
ENSE00003460162	3229095	3229263
ENSE00003510759	3228512	3228707
ENSE00003544133	3228259	3228428
ENSE00003638718	3229524	3229776
ENSE00003645805	3228838	3229011
ENSE00003678112	3229346	3229452
ENSE00003702661	3234568	3234617
ENSE00003704124	3234083	3234314
ENSE00003704700	3233921	3234002
ENSE00003705572	3231330	3231548
ENSE00003707704	3230187	3230260
ENSE00003707733	3230515	3230647
ENSE00003708068	3231149	3231242
ENSE00003709233	3230933	3231058
ENSE00003709645	3230732	3230845
ENSE00003709919	3234742	3234894
ENSE00003709992	3237544	3237588
ENSE00003711236	3233514	3233637
ENSE00003824500	3227422	3227856

Expression profiles

Bgee: expression breadth ubiquitous, 197 present calls, max score 98.42.

FANTOM5 (CAGE): breadth broad, TPM avg 2.3044 / max 117.9466, expressed in 822 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186145	1.5286	712
186146	0.7366	236
186144	0.0392	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	98.42	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.61	gold quality
metanephros cortex	UBERON:0010533	96.43	gold quality
left lobe of thyroid gland	UBERON:0001120	96.41	gold quality
pancreatic ductal cell	CL:0002079	96.04	gold quality
parotid gland	UBERON:0001831	95.82	gold quality
minor salivary gland	UBERON:0001830	95.18	gold quality
thyroid gland	UBERON:0002046	94.59	gold quality
right lobe of thyroid gland	UBERON:0001119	94.41	gold quality
saliva-secreting gland	UBERON:0001044	94.40	gold quality
mouth mucosa	UBERON:0003729	93.21	gold quality
gingival epithelium	UBERON:0001949	92.37	gold quality
mucosa of paranasal sinus	UBERON:0005030	91.15	gold quality
nasal cavity mucosa	UBERON:0001826	90.76	gold quality
bronchial epithelial cell	CL:0002328	90.57	gold quality
lower esophagus mucosa	UBERON:0035834	90.54	gold quality
palpebral conjunctiva	UBERON:0001812	90.39	gold quality
epithelium of nasopharynx	UBERON:0001951	89.81	gold quality
bronchus	UBERON:0002185	89.75	gold quality
esophagus mucosa	UBERON:0002469	88.36	gold quality
gingiva	UBERON:0001828	87.79	gold quality
skin of leg	UBERON:0001511	86.08	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	85.00	gold quality
skin of abdomen	UBERON:0001416	84.69	gold quality
metanephros	UBERON:0000081	84.68	gold quality
esophagus squamous epithelium	UBERON:0006920	84.14	gold quality
zone of skin	UBERON:0000014	84.07	gold quality
right adrenal gland cortex	UBERON:0035827	83.16	gold quality
upper arm skin	UBERON:0004263	83.04	silver quality
oral cavity	UBERON:0000167	82.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.56

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

16 targeting SLC4A11, 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-4668-3P	100.00	68.74	2635
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-6731-5P	99.28	67.42	2375
HSA-MIR-8085	99.28	67.56	2362
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-6871-5P	98.90	66.67	671
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-4509	96.19	65.80	900
HSA-MIR-4431	90.07	69.53	39

Literature-anchored findings (GeneRIF, showing 40)

• The corneal dystrophy and perceptive deafness (Harboyan syndrome) gene (CDPD1) maps to chromosome 20p13. (PMID:11836359)
• congenital hereditary endothelial dystrophy 1 (CHED1) and CHED2 loci on chromosome 20 and the collagen, type VIII, alpha-2 (COL8A2) gene were excluded by linkage and haplotype analyses. (PMID:12654361)
• describe seven different mutations in the SLC4A11 gene in ten families with autosomal recessive congenital hereditary endothelial dystrophy (PMID:16767101)
• These results confirm that mutations in the SLC4A11 gene cause autosomal recessive corneal endothelial dystrophy. (PMID:16825429)
• These findings extend the implication of the SLC4A11 borate transporter beyond corneal dystrophy to perceptive deafness. (PMID:17220209)
• Novel indel mutation, c.859_862delGAGAinsCCT (E287fsX21) in exon 8 of SLC4A11 gene. Novel in-frame deletion mutation c.2014_2016delTTC or 2017_2019delTTC which will lead to loss of a phenylalanine residue at position 672 or 673 (F672del or F673del). (PMID:17262014)
• report of seven novel mutations and two previously identified mutations in families from India and the United Kingdom with recessive congenital hereditary endothelial dystrophy (PMID:17397048)
• CHED2 (congenital hereditary endothelial dystrophy) is associated with mutations in SLC4A11, a member of the SLC4 family of base transporters. (PMID:17667634)
• These data add to the mutational repertoire of SLC4A11 and establish the high degree of mutational heterogeneity in autosomal recessive congenital hereditary endothelial dystrophy. (PMID:17679935)
• SLC4A11 mutations in Fuchs’ endothelial corneal dystrophy are reported. (PMID:18024964)
• A novel SLC4A11 mutation (Thr271Met) is associated with autosomal recessive congenital hereditary endothelial dystrophy in a pedigree from the Kingdom of Saudi Arabia and provides additional support that mutations in this gene cause disease. (PMID:18363173)
• This study increases the number of SLC4A11 gene mutations and confirms the role of this gene in causing congenital hereditary endothelial dystrophy (CHED2). (PMID:18474783)
• In this small cohort, no evidence was found of genetic heterogeneity in congenital hereditary endothelial dystrophy (CHED) and that loss of BTR1 function is the most likely mutational mechanism. (PMID:19369245)
• Corneal endothelial cells are more vulnerable to defects in the functional activity of SLC4A11 than cells of the striae vascularis of the inner ear. (PMID:20118786)
• sequenced SLC4A11 in 192 sporadic and small nuclear late-onset Fuchs corneal dystrophy families and found seven heterozygous missense novel variations that were absent from ethnically matched controls (PMID:20848555)
• The present study detected one novel and three reported changes, adding to the repertoire of mutations in SLC4A11, and recorded a high degree of genetic heterogeneity in Congenital Hereditary Endothelial Dystrophy. (PMID:21203343)
• biochemical study of SLC4A11 (PMID:21288032)
• The reduction in movement of WT SLC4A11 protein to the cell surface caused by Fuchs endothelial corneal dystrophy SLC4A11 helps to explain the dominant inheritance of this disorder. (PMID:22072594)
• SLC4A11 is necessary for cell survival and may explain the pathologic corneal endothelial cell loss in endotheliopathies due to SLC4A11 mutations. (PMID:22447871)
• Both substitution c.214+242C > T in IL1RN and novel deletion c.2558+149_2558+203del54 in SLC4A11 were observed significantly more frequently in family members with keratoconus. (PMID:23462747)
• To the best of our knowledge, this is the first Korean case of CHED2, confirmed by the c.1239C>A (p.C413*) mutation in the SLC4A11 gene, which has not been previously reported. (PMID:23615275)
• Data shows that the function of SLCA11 is to facilitate the movement of water across the basolateral corneal epithelium. (PMID:23813972)
• SLC4A11 has significant EIPA-sensitive Na(+)-OH(-)(H(+)) and NH4(+) permeability. (PMID:23864606)
• The purpose of this study was to identify the genetic cause of congenital hereditary endothelial dystrophy 2 in six Indian families and catalog all known mutations in the SLC4A11 gene. (PMID:23922488)
• Variation in the COL8A2, SLC4A11, and ZEB1 genes is present in only a small fraction of African American cases and as such does not appear to significantly contribute to the genetic risk of Fuchs endothelial corneal dystrophy. (PMID:24348007)
• Our observations suggest that congenital hereditary endothelial dystrophy caused by homozygous SLC4A11 mutations progresses to Harboyan syndrome, but the severity of this may vary considerably. (PMID:24351571)
• We report a novel nonsense mutation of the SLC4A11 gene in the patient with CHED2. In addition, one of heterozygous carriers in this family showed features of late onset Fuchs endothelial corneal dystrophy. (PMID:24502824)
• SLC4A11 mutations contribute to 11% (5/45) of sporadic late-onset Late-onset Fuchs endothelial corneal dystrophy (FECD) in the cohort studied. (PMID:25007886)
• We have described three affected siblings from a non-consanguineous family with Corneal Endothelial Dystrophy 2. (PMID:25138764)
• Potential therapeutic agents to improve the functional impairment of specific SLC4A11 mutant transporters. (PMID:25394471)
• In contrast to the Slc4a11(-/-) mouse, no abnormalities in daily renal ion excretion or polyuria were observed in the Harboyan syndrome patient. (PMID:25500497)
• We found that cells containing mutant SLC4A11 are more vulnerable to oxidative and mitochondrial damage, less able to overcome oxidative stress through the expression of sufficient levels of antioxidant genes, and are more prone to apoptotic death. (PMID:25811729)
• SLC4A11 is a novel NH3/H+ co-transporter. (PMID:26018076)
• study reports a newly identified mutation (c.2024A>C) in the SLC4A11 gene segregating with the diseased haplotype in two consanguineous Pakistani families (PMID:26286922)
• we review the current knowledge on the role of the SLC4A11 gene, protein, and its mutations in the pathophysiology and clinical presentation of CHED. [review] (PMID:26451371)
• we report posterior polymorphous corneal dystrophy resulting from a de novo mutation in ZEB1. Additionally, we present a congenital hereditary endothelial dystrophy case with a thin Descemet membrane with a novel compound heterozygous SLC4A11 mutation. (PMID:26619383)
• SLC4A11 rs3810560 polymorphism independently affected the sustained viral response rates in chronic hepatitis C patients treated with PEGIFN2b/ribavirin/combination. (PMID:26750805)
• A missense SLC4A11 mutation (Leu843Pro) is responsible for CHED2 in this family; this is the first report of this mutation in a homozygous state. (PMID:27057589)
• Analysis of SLC4A11, ZEB1, LOXHD1, COL8A2 and TCF4 gene sequences in a multi-generational family with late-onset Fuchs corneal dystrophy found no evidence for found polymorophisms causing the disease in this specific pedigree. (PMID:27121161)
• A role of human SLC4A11 in bicarbonate or borate transport. (PMID:27558157)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc4a11	ENSDARG00000075532
mus_musculus	Slc4a11	ENSMUSG00000074796
rattus_norvegicus	Slc4a11	ENSRNOG00000021234
caenorhabditis_elegans		WBGENE00009929

Paralogs (9): SLC4A1 (ENSG00000004939), SLC4A7 (ENSG00000033867), SLC4A8 (ENSG00000050438), SLC4A4 (ENSG00000080493), SLC4A9 (ENSG00000113073), SLC4A3 (ENSG00000114923), SLC4A10 (ENSG00000144290), SLC4A2 (ENSG00000164889), SLC4A5 (ENSG00000188687)

Protein

Protein identifiers

Solute carrier family 4 member 11 — Q8NBS3 (reviewed: Q8NBS3)

Alternative names: Sodium borate cotransporter 1

All UniProt accessions (8): Q8NBS3, A0A2R8Y4A6, A0A2R8Y6X5, A0A2R8Y7S1, A0A2R8YEG3, A0A2R8YFD9, V9GXZ2, V9GYK6

UniProt curated annotations — full annotation on UniProt →

Function. Multifunctional transporter with an impact in cell morphology and differentiation. In the presence of borate B(OH)4(-), acts as a voltage-dependent electrogenic Na(+)-coupled B(OH)4(-) cotransporter controlling boron homeostasis. At early stages of stem cell differentiation, participates in synergy with ITGA5-ITGB1 and ITGAV-ITGB3 integrins and BMPR1A to promote cell adhesion and contractility that drives differentiation toward osteogenic commitment while inhibiting adipogenesis. In the absence of B(OH)4(-), acts as a Na(+)-coupled OH(-) or H(+) permeable channel with implications in cellular redox balance. Regulates the oxidative stress response in corneal endothelium by enhancing antioxidant defenses and protecting cells from reactive oxygen species. In response to hypo-osmotic challenge, also acts as a water permeable channel at the basolateral cell membrane of corneal endothelial cells and facilitates transendothelial fluid reabsorption in the aqueous humor. In the presence of ammonia, acts as an electrogenic NH3/H(+) cotransporter and may play a role in ammonia transport and reabsorption in renal Henle’s loop epithelium.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane. Basolateral cell membrane.

Tissue specificity. Widely expressed. Highly expressed in kidney, testis, salivary gland, thyroid, trachea and corneal endothelium. Not detected in retina and lymphocytes. Expressed in corneal endothelium (at protein level). The predominant isoform in corneal endothelium (at protein level). Low expression levels, if any, in cornea.

Post-translational modifications. Glycosylated.

Disease relevance. Corneal dystrophy and perceptive deafness (CDPD) [MIM:217400] An ocular disease characterized by the association of corneal clouding with progressive perceptive hearing loss. The disease is caused by variants affecting the gene represented in this entry. Corneal endothelial dystrophy (CHED) [MIM:217700] A congenital corneal dystrophy characterized by thickening and opacification of the cornea, altered morphology of the endothelium, and secretion of an abnormal collagenous layer at the Descemet membrane. The disease is caused by variants affecting the gene represented in this entry. Corneal dystrophy, Fuchs endothelial, 4 (FECD4) [MIM:613268] A corneal disease caused by loss of endothelium of the central cornea. It is characterized by focal wart-like guttata that arise from Descemet membrane and develop in the central cornea, epithelial blisters, reduced vision and pain. Descemet membrane is thickened by abnormal collagenous deposition. The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated upon oxidative stress, as it occurs in cells exposed to tert-butyl hydroperoxide.

Miscellaneous. Isoforms 1 and 5 are produced by the usage of alternative translation start sites of the same transcript. There is no evidence for isoform 1 expression in cornea (at protein level).

Similarity. Belongs to the anion exchanger (TC 2.A.31) family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q8NBS3-3	3, SLC4A11-v3	yes
Q8NBS3-1	1, SLC4A11-v2-M1
Q8NBS3-2	2
Q8NBS3-4	4, SLC4A11-v1
Q8NBS3-5	5, SLC4A11-v2-M36

RefSeq proteins (8): NP_001167560, NP_001167561, NP_001350674, NP_001387206, NP_001387207, NP_001387208, NP_001387209, NP_114423 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003020	HCO3_transpt_euk	Family
IPR011531	HCO3_transpt-like_TM_dom	Domain
IPR016152	PTrfase/Anion_transptr	Homologous_superfamily

Pfam: PF00955

Catalyzed reactions (Rhea), 1 shown:

• tetrahydroxoborate(in) + 2 Na(+)(in) = tetrahydroxoborate(out) + 2 Na(+)(out) (RHEA:66816)

UniProt features (144 total): sequence variant 53, helix 32, topological domain 15, transmembrane region 14, strand 12, turn 5, sequence conflict 5, splice variant 4, glycosylation site 2, chain 1, mutagenesis site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7X1J	ELECTRON MICROSCOPY	2.84
7X1G	ELECTRON MICROSCOPY	2.94
7X1I	ELECTRON MICROSCOPY	2.94
7X1H	ELECTRON MICROSCOPY	2.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NBS3-F1	74.36	0.20

Functional residue map

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

Glycosylation sites (2): 529, 537

Mutagenesis-validated functional residues (1):

Position	Phenotype
623	decreases the water flux across the plasma membrane.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 176 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, AP1_01, PEREZ_TP63_TARGETS, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, AREB6_01, GOBP_INORGANIC_ANION_TRANSPORT, USF_C, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_WATER_TRANSPORT, AP1_Q4_01, BACH2_01, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_BICARBONATE_TRANSPORT, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, TGANTCA_AP1_C

GO Biological Process (18): sodium ion transport (GO:0006814), monoatomic anion transport (GO:0006820), bicarbonate transport (GO:0015701), intracellular monoatomic cation homeostasis (GO:0030003), cellular response to oxidative stress (GO:0034599), fluid transport (GO:0042044), borate transport (GO:0046713), monoatomic ion homeostasis (GO:0050801), regulation of mitochondrial membrane potential (GO:0051881), transmembrane transport (GO:0055085), cellular hypotonic response (GO:0071476), proton transmembrane transport (GO:1902600), regulation of mesenchymal stem cell differentiation (GO:2000739), monoatomic ion transport (GO:0006811), water transport (GO:0006833), inorganic anion transport (GO:0015698), borate transmembrane transport (GO:0035445), sodium ion transmembrane transport (GO:0035725)

GO Molecular Function (11): sodium channel activity (GO:0005272), water transmembrane transporter activity (GO:0005372), solute:inorganic anion antiporter activity (GO:0005452), proton transmembrane transporter activity (GO:0015078), bicarbonate transmembrane transporter activity (GO:0015106), proton channel activity (GO:0015252), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857), obsolete active borate transmembrane transporter activity (GO:0046715), protein dimerization activity (GO:0046983), antiporter activity (GO:0015297)

GO Cellular Component (5): plasma membrane (GO:0005886), vesicle membrane (GO:0012506), basolateral plasma membrane (GO:0016323), apical plasma membrane (GO:0016324), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	5
monoatomic cation transmembrane transport	2
transmembrane transport	2
monoatomic cation channel activity	2
transmembrane transporter activity	2
secondary active transmembrane transporter activity	2
plasma membrane region	2
metal ion transport	1
monoatomic ion transport	1
intracellular monoatomic ion homeostasis	1
monoatomic cation homeostasis	1
response to oxidative stress	1
cellular response to chemical stress	1
inorganic anion transport	1
chemical homeostasis	1
regulation of membrane potential	1
cellular process	1
hypotonic response	1
cellular response to osmotic stress	1
mesenchymal stem cell differentiation	1
regulation of stem cell differentiation	1
fluid transport	1
borate transport	1
sodium ion transport	1
sodium ion transmembrane transporter activity	1
water transport	1
antiporter activity	1
monoatomic cation transmembrane transporter activity	1
proton transmembrane transport	1
bicarbonate transport	1
proton transmembrane transporter activity	1
transporter activity	1
protein binding	1
membrane	1
cell periphery	1
organelle membrane	1
vesicle	1
basal plasma membrane	1
apical part of cell	1
cellular anatomical structure	1

Protein interactions and networks

STRING

828 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC4A11	COL8A2	P25067	962
SLC4A11	AGBL1	Q96MI9	808
SLC4A11	LOXHD1	Q8IVV2	799
SLC4A11	ZEB1	P37275	784
SLC4A11	TCF4	P15884	755
SLC4A11	CYYR1	Q96J86	647
SLC4A11	CHST6	Q9GZX3	605
SLC4A11	KANK4	Q5T7N3	570
SLC4A11	VSX1	Q9NZR4	544
SLC4A11	B3GLCT	Q6Y288	538
SLC4A11	KERA	O60938	484
SLC4A11	UBIAD1	Q9Y5Z9	482
SLC4A11	TGFBI	Q15582	458
SLC4A11	ZNF469	Q96JG9	448
SLC4A11	TMEM178A	Q8NBL3	443

IntAct

5 interactions, top by confidence:

A	B	Type	Score
SLC4A11	H3-4	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
SLC4A11	VAPB	psi-mi:“MI:0914”(association)	0.350

BioGRID (13): SLC4A11 (Proximity Label-MS), SLC4A11 (Affinity Capture-MS), SLC4A11 (Affinity Capture-MS), SLC4A11 (Cross-Linking-MS (XL-MS)), PRPF19 (Cross-Linking-MS (XL-MS)), BAG5 (Affinity Capture-MS), FTSJ1 (Affinity Capture-MS), SNTB2 (Affinity Capture-MS), THEM6 (Affinity Capture-MS), TMEM33 (Affinity Capture-MS), VAPA (Affinity Capture-MS), VAPB (Affinity Capture-MS), WDR6 (Affinity Capture-MS)

ESM2 similar proteins: A0A452G813, A0A8V0ZB02, A2AJN7, A2AWR3, A9LIW2, B1WB39, B6HTR9, D3ZNF5, F4I248, F4JCY2, O23693, O57428, O77761, O94886, Q06538, Q0VGV9, Q12791, Q17JQ7, Q3KTM2, Q3TWI9, Q4R7U0, Q4V8U5, Q5GH60, Q5GH68, Q5R826, Q5R9A7, Q5T3F8, Q5YCC5, Q62976, Q6NP91, Q6PP77, Q7SYR6, Q7Z3F1, Q7Z402, Q7ZYA0, Q8BH79, Q8C428, Q8CBX0, Q8GUH7, Q8NBS3

Diamond homologs: A2AJN7, P02730, P04920, P13808, P15575, P23347, P48746, Q2Y0W8, Q5RD44, Q6RVG2, Q6SJP2, Q80ZA5, Q8JZR6, Q8NBS3, Q9Z0S8, A0A494BA31, B1MTL0, P48751

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

1294 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	81
Likely pathogenic	75
Uncertain significance	266
Likely benign	720
Benign	44

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068399	NM_001174089.2(SLC4A11):c.2402dup (p.Thr802fs)	Pathogenic
1068587	NM_001174089.2(SLC4A11):c.1349G>A (p.Trp450Ter)	Pathogenic
1069511	NM_001174089.2(SLC4A11):c.286C>T (p.Arg96Ter)	Pathogenic
1070365	NM_001174089.2(SLC4A11):c.1915del (p.Ser638_Leu639insTer)	Pathogenic
1070390	NC_000020.10:g.(?3215204)(3219846_?)del	Pathogenic
1070391	NC_000020.10:g.(?3214150)(3219846_?)del	Pathogenic
1070931	NM_001174089.2(SLC4A11):c.912del (p.Ser305fs)	Pathogenic
1071834	NM_001174089.2(SLC4A11):c.669dup (p.Trp224fs)	Pathogenic
1075409	NM_001174089.2(SLC4A11):c.672G>A (p.Trp224Ter)	Pathogenic
1076868	NM_001174089.2(SLC4A11):c.1632del (p.Thr545fs)	Pathogenic
1184523	NM_001174089.2(SLC4A11):c.1658C>A (p.Ser553Ter)	Pathogenic
1304	NM_001174089.2(SLC4A11):c.2216G>A (p.Arg739Gln)	Pathogenic
1306	NM_001174089.2(SLC4A11):c.1343G>A (p.Gly448Asp)	Pathogenic
1307	NM_001174089.2(SLC4A11):c.1765C>T (p.Arg589Ter)	Pathogenic
1308	NM_001174089.2(SLC4A11):c.305_308del (p.Lys102fs)	Pathogenic
1310	NM_001174089.2(SLC4A11):c.2019-16_2019-6delinsGGCCGGCCGG	Pathogenic
1312	NM_001174089.2(SLC4A11):c.425_432del (p.Arg142fs)	Pathogenic
1313	NM_001174089.2(SLC4A11):c.1330_1333delinsA (p.Tyr444_Ala445delinsThr)	Pathogenic
1314	NM_001174089.2(SLC4A11):c.1415G>A (p.Arg472Lys)	Pathogenic
1318	NM_032034.4:c.2423_2454del	Pathogenic
1356826	NM_001174089.2(SLC4A11):c.2185_2192dup (p.Ile732fs)	Pathogenic
1368491	NM_001174089.2(SLC4A11):c.953del (p.Pro318fs)	Pathogenic
1377925	NM_001174089.2(SLC4A11):c.2317_2327del (p.Leu773fs)	Pathogenic
1386023	NM_001174089.2(SLC4A11):c.696_700del (p.Phe233fs)	Pathogenic
1414795	NM_001174089.2(SLC4A11):c.582C>A (p.Tyr194Ter)	Pathogenic
1416458	NM_001174089.2(SLC4A11):c.577C>T (p.Arg193Trp)	Pathogenic
1427836	NM_001174089.2(SLC4A11):c.139del (p.Leu47fs)	Pathogenic
1442474	NM_001174089.2(SLC4A11):c.187G>T (p.Glu63Ter)	Pathogenic
1443419	NM_001174089.2(SLC4A11):c.44-81_44-74del	Pathogenic
1452930	NM_001174089.2(SLC4A11):c.2350C>T (p.Gln784Ter)	Pathogenic

SpliceAI

3160 predictions. Top by Δscore:

Variant	Effect	Δscore
20:3227852:TATAG:T	acceptor_gain	1.0000
20:3227853:ATAG:A	acceptor_gain	1.0000
20:3227854:TAG:T	acceptor_gain	1.0000
20:3227854:TAGC:T	acceptor_loss	1.0000
20:3227856:GCTG:G	acceptor_loss	1.0000
20:3227857:C:CC	acceptor_gain	1.0000
20:3227857:CTGT:C	acceptor_loss	1.0000
20:3227858:T:A	acceptor_loss	1.0000
20:3228302:T:TA	donor_gain	1.0000
20:3228425:CAGT:C	acceptor_gain	1.0000
20:3228429:C:CC	acceptor_gain	1.0000
20:3228507:CTCA:C	donor_loss	1.0000
20:3228508:TCAC:T	donor_loss	1.0000
20:3228509:CAC:C	donor_loss	1.0000
20:3228510:A:AC	donor_gain	1.0000
20:3228511:C:CC	donor_gain	1.0000
20:3228511:C:CT	donor_loss	1.0000
20:3228511:CCTG:C	donor_gain	1.0000
20:3228703:CAATC:C	acceptor_gain	1.0000
20:3228706:TC:T	acceptor_gain	1.0000
20:3228706:TCC:T	acceptor_loss	1.0000
20:3228707:CC:C	acceptor_gain	1.0000
20:3228707:CCT:C	acceptor_loss	1.0000
20:3228708:C:CA	acceptor_loss	1.0000
20:3228708:C:CC	acceptor_gain	1.0000
20:3228836:A:AC	donor_gain	1.0000
20:3228837:C:CC	donor_gain	1.0000
20:3228837:CGTGT:C	donor_gain	1.0000
20:3228938:C:CT	acceptor_gain	1.0000
20:3228938:C:T	acceptor_gain	1.0000

AlphaMissense

5725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:3233934:A:G	W214R	0.998
20:3233934:A:T	W214R	0.998
20:3231517:C:G	R270P	0.997
20:3231537:C:A	K263N	0.997
20:3231537:C:G	K263N	0.997
20:3228369:G:C	F832L	0.995
20:3228369:G:T	F832L	0.995
20:3228371:A:G	F832L	0.995
20:3231508:G:T	A273D	0.995
20:3228367:G:T	T833K	0.994
20:3228982:T:G	D699A	0.994
20:3230574:A:C	S468R	0.994
20:3230574:A:T	S468R	0.994
20:3230576:T:G	S468R	0.994
20:3228573:G:T	A792E	0.993
20:3228929:A:G	W717R	0.993
20:3228929:A:T	W717R	0.993
20:3230582:A:G	W466R	0.993
20:3230582:A:T	W466R	0.993
20:3234584:A:G	L108P	0.993
20:3228289:G:C	P859R	0.992
20:3228370:A:G	F832S	0.992
20:3228591:C:T	G786D	0.992
20:3228685:G:C	R755G	0.992
20:3228883:A:G	L732P	0.992
20:3228896:G:C	H728D	0.992
20:3228982:T:A	D699V	0.992
20:3228986:A:G	W698R	0.992
20:3228986:A:T	W698R	0.992
20:3230974:G:T	A392D	0.992

dbSNP variants (sampled 300 via entrez): RS1000161043 (20:3239926 T>A), RS1000214377 (20:3239730 G>A), RS1001041041 (20:3229129 A>G), RS1001283161 (20:3237584 G>A,C), RS1001479491 (20:3233400 G>A), RS1001688908 (20:3232026 G>A), RS1001894363 (20:3240811 A>C,G), RS1002905775 (20:3241008 T>C,G), RS1002956893 (20:3238627 T>C), RS1003009200 (20:3238395 G>A,C), RS1003028419 (20:3235792 C>T), RS1003140237 (20:3230919 C>T), RS1003306682 (20:3233477 C>G), RS1003318204 (20:3237360 C>G), RS1003409298 (20:3228773 T>C)

Disease associations

OMIM: gene MIM:610206 | disease phenotypes: MIM:217400, MIM:217700, MIM:613268, MIM:122000

GenCC curated gene-disease

Disease	Classification	Inheritance
corneal dystrophy-perceptive deafness syndrome	Strong	Autosomal recessive
congenital hereditary endothelial dystrophy of cornea	Strong	Autosomal recessive
corneal dystrophy, Fuchs endothelial, 4	Strong	Autosomal dominant
Fuchs’ endothelial dystrophy	Supportive	Autosomal dominant

Mondo (6): corneal dystrophy-perceptive deafness syndrome (MONDO:0009015), congenital hereditary endothelial dystrophy of cornea (MONDO:0009019), corneal dystrophy, Fuchs endothelial, 4 (MONDO:0013204), corneal dystrophy (MONDO:0018102), posterior polymorphous corneal dystrophy 1 (MONDO:0007378), Fuchs’ endothelial dystrophy (MONDO:0005321)

Orphanet (5): Corneal dystrophy-perceptive deafness syndrome (Orphanet:1490), Congenital hereditary endothelial dystrophy type II (Orphanet:293603), Fuchs endothelial corneal dystrophy (Orphanet:98974), Corneal dystrophy (Orphanet:34533), Posterior polymorphous corneal dystrophy (Orphanet:98973)

HPO phenotypes

23 total (23 of 23 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000505	Visual impairment
HP:0000572	Visual loss
HP:0000622	Blurred vision
HP:0000639	Nystagmus
HP:0000662	Nyctalopia
HP:0000969	Edema
HP:0001131	Corneal dystrophy
HP:0007663	Reduced visual acuity
HP:0007759	Opacification of the corneal stroma
HP:0007957	Corneal opacity
HP:0011462	Young adult onset
HP:0011487	Increased corneal thickness
HP:0011488	Abnormal corneal endothelium morphology
HP:0011490	Abnormal Descemet membrane morphology
HP:0011491	Reduced number of corneal endothelial cells
HP:0012038	Corneal guttata
HP:0012040	Corneal stromal edema
HP:0030857	Eye movement-induced pain
HP:0031792	Irregular astigmatism
HP:0410280	Pediatric onset

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST003542_168	Night sleep phenotypes	9.000000e-06
GCST005212_27	Asthma	7.000000e-06
GCST009613_3	HDL cholesterol levels x loop diuretics use interaction	3.000000e-07
GCST010002_59	Refractive error	6.000000e-11
GCST012442_8	Age-related hearing impairment	5.000000e-08
GCST012490_143	Femur bone mineral density x serum urate levels interaction	3.000000e-08
GCST90002387_154	Immature fraction of reticulocytes	9.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003317	Corneal Dystrophies, Hereditary	C11.204.236; C11.270.162; C16.320.290.162
D005642	Fuchs’ Endothelial Dystrophy	C11.204.236.438; C11.270.162.438; C16.320.290.162.410
C567677	Corneal Dystrophy, Fuchs Endothelial, 4 (supp.)
C535473	Corneal dystrophy and perceptive deafness (supp.)
C536439	Corneal endothelial dystrophy type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — Sodium-dependent HCO₃^- transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, increases methylation, affects cotreatment	8
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	5
Benzo(a)pyrene	increases expression	4
Aflatoxin B1	increases expression	4
bisphenol A	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	2
sotorasib	affects cotreatment, increases expression	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
lead acetate	decreases expression	1
trichostatin A	increases expression	1
arsenite	decreases expression, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
nickel sulfate	decreases expression	1
perfluorooctane sulfonic acid	increases expression	1
monomethylarsonous acid	decreases expression	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
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Vorinostat	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4PN	HCT116-SLC4A11-KO-c6	Cancer cell line	Male
CVCL_D4PP	HCT116-SLC4A11-KO-c9	Cancer cell line	Male
CVCL_TN88	HAP1 SLC4A11 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05136443	PHASE4	COMPLETED	Loteprednol Etabonate 0.25% for Prevention of Cornea Transplant Rejection
NCT00781027	PHASE4	COMPLETED	Fuchs’ Torsional Phaco Study
NCT03249337	PHASE4	RECRUITING	Glanatec(R) for Descemet Stripping in Fuch’s Endothelial Dystrophy
NCT05716945	PHASE4	RECRUITING	The OPTIMISE Study
NCT03248037	PHASE3	COMPLETED	Trial of Netarsudil for Prevention of Corticosteroid-induced Intraocular Pressure Elevation
NCT05275972	PHASE3	RECRUITING	Descemet Endothelial Thickness Comparison Trial II
NCT06048380	PHASE3	RECRUITING	The Effects of Ripasudil in Patients With FED Undergoing Femtosecond Laser Assisted Cataract Surgery
NCT03575130	PHASE2	UNKNOWN	Ripasudil 0.4% Eye Drops in Fuchs Endothelial Corneal Dystrophy
NCT04812067	PHASE2	COMPLETED	A Safety and Efficacy Trial of TTHX1114 in People With CED
NCT04843839	PHASE2	UNKNOWN	CHED - Congenital Hereditary Endothelial Dystrophy: New Paradigm Shift in Therapy Using Topical Eye Drops
NCT02834260	PHASE2	COMPLETED	Immunosuppression During Penetrating Keratoplasty, Using a Subconjunctival Implant Releasing Dexamethasone : Tolerance and Safety Pilot Study
NCT03813056	PHASE2	UNKNOWN	Ripasudil for Enhanced Corneal Clearing Following Descemet Membrane Endothelial Keratoplasty in Fuchs’ Dystrophy
NCT04676737	PHASE2	COMPLETED	TTHX1114(NM141) in Combination With DWEK/DSO
NCT05279157	PHASE2	COMPLETED	Autologous Adipose-Derived Adult Stem Cell Implantation for Corneal Diseases (ADASCs-CT-CD)
NCT04191629	PHASE1	UNKNOWN	Phase 1 Study to Evaluate the Safety and Tolerability of EO1404 in the Treatment of Corneal Edema
NCT04894110	PHASE1	COMPLETED	Study of Safety and Tolerability of EO2002 in the Treatment of Corneal Edema
NCT05636579	PHASE1	RECRUITING	Study to Assess Safety and Tolerability of Multiple Doses of EO2002
NCT04319848	PHASE1	RECRUITING	Safety and Efficacy of Tissue Engineered Endothelial Keratoplasty
NCT07325097	PHASE1	RECRUITING	PVEK Corneal Implant For Treatment of Corneal Edema
NCT04520321	PHASE1/PHASE2	COMPLETED	A Phase 1/ Phase 2 Study of TTHX1114(NM141)
NCT03971357	PHASE2/PHASE3	TERMINATED	Trial of Netarsudil for Acceleration of Corneal Endothelial Restoration
NCT04018417	PHASE2/PHASE3	WITHDRAWN	Evaluation of Amphotericin B in Optisol-GS for Prevention of Post-Keratoplasty Fungal Infections.
NCT04051463	PHASE2/PHASE3	COMPLETED	Rhopressa for Corneal Edema Associated With Fuchs Dystrophy
NCT03275896	EARLY_PHASE1	UNKNOWN	Evaluation of the Efficacy of Descemet Membrane Transplantation for the Treatment of Fuchs’ Endothelial Dystrophy
NCT04057053	EARLY_PHASE1	COMPLETED	Netarsudil Use After Descemetorhexis Without Endothelial Keratoplasty
NCT04752020	EARLY_PHASE1	COMPLETED	Netarsudil Use After Descemtorhexis Without Endothelial Keratoplasty
NCT00624221	Not specified	COMPLETED	Study of Eye Bank Pre-cut Donor Grafts for Endothelial Keratoplasty
NCT01206127	Not specified	UNKNOWN	DSAEK- Postoperative Positioning and Transplant Dislocation
NCT01361282	Not specified	TERMINATED	Using the Optovue OCT to Select IOL Power
NCT01586234	Not specified	TERMINATED	OCT-guided DSAEK Graft Shaping and Smoothing
NCT01795001	Not specified	COMPLETED	The Molecular Pathogenesis of Late-onset Fuchs’ Endothelial Corneal Dystrophy
NCT02118922	Not specified	RECRUITING	A Study to Test the Diagnostic Potential of Brillouin Microscopy for Corneal Ectasia
NCT02332109	Not specified	COMPLETED	ODM 5 in the Treatment of Corneal Edematous Fuchs’ Endothelial Dystrophy
NCT02423161	Not specified	COMPLETED	PIONEER: Intraoperative and Perioperative OCT Study
NCT02423213	Not specified	RECRUITING	DISCOVER Study: Microscope-integrated Intraoperative OCT Study
NCT02470793	Not specified	COMPLETED	Technique And Results In Endothelial Keratoplasty
NCT02542644	Not specified	COMPLETED	Assessment of Corneal Graft Attachment in Patients With Fuchs Endothelial Corneal Dystrophy Following DMEK Using Ultra-high Resolution OCT
NCT02793310	Not specified	COMPLETED	DMEK Versus DSAEK Study
NCT02849808	Not specified	COMPLETED	Long Term Cornea Graft Survival Study
NCT02875145	Not specified	COMPLETED	Impact of Cataract Surgery on Keratoplasty Graft Survival