SLC5A5

Summary

SLC5A5 (solute carrier family 5 member 5, HGNC:11040) is a protein-coding gene on chromosome 19p13.11, encoding Sodium/iodide cotransporter (Q92911). Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland.

This gene encodes a member of the sodium glucose cotransporter family. The encoded protein is responsible for the uptake of iodine in tissues such as the thyroid and lactating breast tissue. The iodine taken up by the thyroid is incorporated into the metabolic regulators triiodothyronine (T3) and tetraiodothyronine (T4). Mutations in this gene are associated with thyroid dyshormonogenesis 1.

Source: NCBI Gene 6528 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thyroid dyshormonogenesis 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 576 total — 27 pathogenic, 28 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_000453

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11040
Approved symbol	SLC5A5
Name	solute carrier family 5 member 5
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	NIS
Ensembl gene	ENSG00000105641
Ensembl biotype	protein_coding
OMIM	601843
Entrez	6528

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 retained_intron

ENST00000222248, ENST00000597109

RefSeq mRNA: 1 — MANE Select: NM_000453 NM_000453

CCDS: CCDS12368

Canonical transcript exons

ENST00000222248 — 15 exons

Exon	Start	End
ENSE00000689848	17874138	17874203
ENSE00000689849	17874494	17874545
ENSE00000689850	17874664	17874731
ENSE00000689852	17875952	17876106
ENSE00000689853	17877723	17877863
ENSE00000689854	17877964	17878093
ENSE00000689855	17880865	17880953
ENSE00000689856	17881960	17882072
ENSE00000689857	17882149	17882219
ENSE00000689860	17888331	17888455
ENSE00000689861	17890886	17891001
ENSE00000871060	17871945	17872676
ENSE00001213003	17893713	17895174
ENSE00003615706	17883681	17883767
ENSE00003636196	17883850	17884046

Expression profiles

Bgee: expression breadth broad, 85 present calls, max score 91.52.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9070 / max 299.0324, expressed in 87 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174556	0.8844	85
174559	0.0226	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
olfactory bulb	UBERON:0002264	91.52	gold quality
type B pancreatic cell	CL:0000169	91.22	gold quality
mucosa of stomach	UBERON:0001199	84.60	gold quality
thymus	UBERON:0002370	80.78	gold quality
pancreatic ductal cell	CL:0002079	80.74	silver quality
hair follicle	UBERON:0002073	80.74	gold quality
vena cava	UBERON:0004087	80.33	gold quality
body of tongue	UBERON:0011876	78.00	gold quality
epithelium of nasopharynx	UBERON:0001951	77.66	gold quality
trachea	UBERON:0003126	77.45	gold quality
cardia of stomach	UBERON:0001162	76.83	gold quality
pharyngeal mucosa	UBERON:0000355	76.63	gold quality
tongue	UBERON:0001723	76.61	gold quality
deltoid	UBERON:0001476	76.30	silver quality
cerebellar vermis	UBERON:0004720	76.25	gold quality
substantia nigra pars reticulata	UBERON:0001966	76.05	gold quality
superior surface of tongue	UBERON:0007371	76.03	gold quality
inferior vagus X ganglion	UBERON:0005363	75.96	gold quality
ileal mucosa	UBERON:0000331	75.93	gold quality
lateral nuclear group of thalamus	UBERON:0002736	75.90	gold quality
tibialis anterior	UBERON:0001385	75.89	silver quality
pericardium	UBERON:0002407	75.77	gold quality
lateral globus pallidus	UBERON:0002476	75.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	75.71	gold quality
nipple	UBERON:0002030	75.68	gold quality
pons	UBERON:0000988	75.60	gold quality
triceps brachii	UBERON:0001509	75.59	gold quality
saphenous vein	UBERON:0007318	75.55	gold quality
substantia nigra pars compacta	UBERON:0001965	75.45	gold quality
pylorus	UBERON:0001166	75.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APEX1, BRAF, CEBPB, CREB1, CREM, EGR1, ESR1, FOXA2, FOXE1, HHEX, NKX2-1, NKX2-5, PARP1, PAX8, PPARG, SMAD3, SP1, SSRP1, TFAP2A, TGFB1, TP53, TP73, TSHB, TTF1, WT1, ZNF395

miRNA regulators (miRDB)

77 targeting SLC5A5, 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-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459

Literature-anchored findings (GeneRIF, showing 40)

• iodide symporter gene expression in JAr cells is regulated by human chorionic gonadotropin and by cAMP-dependent and -independent mechanisms; the stimulation of iodide uptake is due to an increase in both mRNA and protein levels (PMID:12021185)
• Data show that sodium-iodide symporter promoter/luciferase reporter constructs had increased transcriptional activity after incubation with T3 or RA. (PMID:12039073)
• A novel peculiar mutation in the sodium/iodide symporter gene in spanish siblings with iodide transport defect. (PMID:12161518)
• A far-upstream enhancer is important for hNIS regulation in the thyroid. Deficient CRE-like sequence binding protein(s) that bind to the hNUE in normal thyroid cells may be responsible for reduced NIS gene expression in some thyroid carcinomas. (PMID:12351692)
• observations raise the possibility that NIS expression, and subsequently iodide transport, are reduced in thyroid tumors at least in part owing to alterations in the binding activity of AP2 and Sp1 transcription factors to NIS promoter (PMID:12475396)
• Expression of NIS RNA and protein was confirmed by RNAase protection assay, western blot and immunohistochemistry respectively in surgically excised breast tumor tissue (infiltrating duct carcinoma) (PMID:12602914)
• sodium iodide symporter is present in many normal epithelial tissues and is predominantly expressed intracellularly in many carcinomas (PMID:12679487)
• NIS mRNA levels did not differ in adenomas or carcinomas, compared with normal tissue, and no significant relationship with levels of CREB mRNA was observed. (PMID:12720543)
• role for APE/Ref-1 protein in the transcriptional regulation of NIS gene expression by itself and in cooperation with PAX8. (PMID:14630715)
• Rat and human 5’ flanking regions in the thyroid share only a 67.8 per cent identity. (PMID:15009910)
• organification of radioiodide into proteins of thyroid cancer cells exogenously co-expressing TPO and the sodium/iodide symporter (NIS) is strictly dependent of TPO and not of NIS. (PMID:15062578)
• hNIS promoter and enhancer showed an up to six-fold increase in transcriptional activity after incubation with purified Graves’ IgG (PMID:15062579)
• that NIS protein expression does not reflect NIS mRNA expression. Therefore, factors that affect targeting of NIS to the plasma membrane are likely to be affected. (PMID:15068624)
• NIS was found only in malignant thyroid neoplasms and in euthyroid patients; none was found in hypofunctioning thyroid tumors. (PMID:15215159)
• Nkx-2.5 is a novel relevant transcriptional regulator of mammary NIS (PMID:15340050)
• NIS expression is induced by cAMP and/or PI3K in breast cancer both in vivo and in vitro. (PMID:15472226)
• Data show that tumor cells expressing the thyroidal sodium iodide symporter (NIS) retain iodide longer than thyroid cells due to a combination of slow efflux and reuptake. (PMID:15522214)
• Hypothyroidism during type I interferon therapy may be related to an abnormal expression and function of key proteins involved in iodine uptake and organification. (PMID:15562032)
• control of NIS expression by inhibition of histone deacetylases appears not to be mediated by cell-specific mechanisms (PMID:15919754)
• Molecular analysis of the expression of the sodium iodide symporter with differentiated thyroid cancer and correlation with scintigraphic findings. (PMID:15968416)
• G543 residue plays significant roles in NIS maturation and trafficking. (PMID:15976004)
• NIS gene expression has beneficial effects in human anaplastic thyroid carcinoma cells (PMID:16264365)
• Our results suggest that there is no dependence between NIS expression and iodine uptake in thyroid cancers. (PMID:16335670)
• Our study suggests that NIS will be useful as an imaging reporter gene to ascertain that the therapeutic gene is localized to the correct tissue and to monitor the expression levels and duration of the therapeutic gene. (PMID:16391203)
• Agents that promote tumor differentiation, or directly stimulate gene expression may result in iodine concentration in ‘scan-negative’ thyroid cancer and some breast cancer. (review) (PMID:16954431)
• These data show for the first time that functional NIS expression is not restricted to lactating mammary gland and malignant breast tissue, but can also be detected in benign breast lesions, such as fibroadenomata of the breast. (PMID:16982034)
• Recent findings in NIS research that have a direct impact on diagnosis and therapeutic management. (PMID:16990649)
• Protein synthesis inhibitors, in synergy with 5-azacytidine, restore sodium/iodide symporter gene expression in thyroid cancer cells. (PMID:17164311)
• Sodium-iodide symporter expression is decreased or absent in cases of intestinalization or malignant transformation of the gastric mucosa. (PMID:17214887)
• overexpression of PTTG and PBF in differentiated thyroid cancer has profound implications for activity of the NIS gene, and hence significantly impacts upon the efficacy of radioiodine treatment. (PMID:17297475)
• A significant proportion of human cholangiocarcinomas expresses membrane sodium iodide symporter, which may permit radioiodine therapy. Our data also suggest that (131)I acts on a crucial target for liver cancer development. (PMID:17408651)
• NIS is adequately expressed and appropriately localized in the thyroid nodule cell membrane from iodine-deficient areas and its expression in vivo is modulated by iodine supply. (PMID:17696829)
• expression of placental NIS is modulated by maternal iodide (PMID:17726079)
• Papillary thyroid cancers Papillary thyroid cancers with no 131I uptake had slightly reduced NIS, significantly reduced thyroglobulin,thyroperoxidase and pendrin and significantly increased GLUT-1 gene expression levels. (PMID:17854396)
• NIS-L methylation in cancer cells was not associated with methylation in adjacent benign tissue, unlike the other 4 genes. (PMID:17938324)
• Evaluation of NIS mRNA expression in thyroid tissues may help determine prognoses of Graves’ disease patients. (PMID:18187871)
• CREM is an essential regulator of NIS gene expression. (PMID:18202121)
• The region of this protein that contains V59 substitution may be involved in intramembrane helix-helix interactions during the transport cycle without being in direct contact with the substrates. (PMID:18339708)
• cell surface trafficking impairments account for variable cell surface sodium iodide symporter levels in breast cancer (PMID:18500672)
• study revealed a significant correlation of BRAFV600E mutation with a lower expression of both sodium iodide symporter and thyroperoxidase in papillary thyroid cancer (PMID:18509003)

Cross-species orthologs

15 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc5a5	ENSDARG00000005392
mus_musculus	Slc5a5	ENSMUSG00000000792
rattus_norvegicus	Slc5a5	ENSRNOG00000018822
drosophila_melanogaster	CG2187	FBGN0017448
drosophila_melanogaster	rumpel	FBGN0029950
drosophila_melanogaster	SLC5A11	FBGN0031998
drosophila_melanogaster	bumpel	FBGN0037895
drosophila_melanogaster	ChT	FBGN0038641
drosophila_melanogaster	salt	FBGN0039872
drosophila_melanogaster	Smvt	FBGN0039873
drosophila_melanogaster	CG31262	FBGN0051262
drosophila_melanogaster	CG31668	FBGN0051668
drosophila_melanogaster	CG33124	FBGN0053124
drosophila_melanogaster	kumpel	FBGN0250757
caenorhabditis_elegans		WBGENE00000501

Paralogs (12): SLC5A1 (ENSG00000100170), SLC5A4 (ENSG00000100191), SLC5A7 (ENSG00000115665), SLC5A9 (ENSG00000117834), SLC5A6 (ENSG00000138074), SLC5A2 (ENSG00000140675), SLC5A12 (ENSG00000148942), SLC5A10 (ENSG00000154025), SLC5A11 (ENSG00000158865), SLC5A3 (ENSG00000198743), SLC5A8 (ENSG00000256870), (ENSG00000293606)

Protein

Protein identifiers

Sodium/iodide cotransporter — Q92911 (reviewed: Q92911)

Alternative names: Natrium iodide transporter, Sodium-iodide symporter, Solute carrier family 5 member 5

All UniProt accessions (1): Q92911

UniProt curated annotations — full annotation on UniProt →

Function. Sodium:iodide symporter that mediates the transport of iodide into the thyroid gland. Can also mediate the transport of chlorate, thiocynate, nitrate and selenocynate.

Subunit / interactions. Monomer.

Subcellular location. Cell membrane. Cytoplasm.

Tissue specificity. Expression is primarily in thyroid tissue, but also to a lower extent in mammary gland and ovary. Expression is reduced in tumors.

Post-translational modifications. Glycosylated.

Disease relevance. Thyroid dyshormonogenesis 1 (TDH1) [MIM:274400] A disorder characterized by the inability of the thyroid to maintain a concentration difference of readily exchangeable iodine between the plasma and the thyroid gland, leading to congenital hypothyroidism. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Dysidenin and perchlorate inhibit iodide transport activity. Oxyanions inhibit iodide transport activity by blocking the binding sites for iodide and one of the sodium ions.

Induction. Up-regulated by forskolin and thyrotropin (at protein level).

Similarity. Belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family.

RefSeq proteins (1): NP_000444* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001734	Na/solute_symporter	Family
IPR018212	Na/solute_symporter_CS	Conserved_site
IPR035689	SLC5A5	Family
IPR038377	Na/Glc_symporter_sf	Homologous_superfamily
IPR051163	Sodium:Solute_Symporter_SSF	Family

Pfam: PF00474

Catalyzed reactions (Rhea), 5 shown:

• iodide(out) + 2 Na(+)(out) = iodide(in) + 2 Na(+)(in) (RHEA:71207)
• chlorate(out) + 2 Na(+)(out) = chlorate(in) + 2 Na(+)(in) (RHEA:71211)
• thiocyanate(out) + 2 Na(+)(out) = thiocyanate(in) + 2 Na(+)(in) (RHEA:71215)
• nitrate(out) + 2 Na(+)(out) = nitrate(in) + 2 Na(+)(in) (RHEA:71219)
• selenocyanate(out) + 2 Na(+)(out) = selenocyanate(in) + 2 Na(+)(in) (RHEA:71227)

UniProt features (62 total): topological domain 14, binding site 14, transmembrane region 13, sequence variant 9, mutagenesis site 6, glycosylation site 2, chain 1, region of interest 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92911-F1	81.54	0.59

Functional residue map

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

Ligand- & substrate-binding residues (14): 69; 71; 72; 72; 76; 90; 144; 144; 255; 258; 413; 416 …

Post-translational modifications (1): 556

Glycosylation sites (2): 489, 502

Mutagenesis-validated functional residues (6):

Position	Phenotype
226	significant loss of iodide transport activity but no effect on its localization to the cell membrane.
237	loss of localization to the cell membrane, significant loss of iodide transport activity but no effect on homodimerizati
242	loss of localization to the cell membrane, significant loss of iodide transport activity but no effect on homodimerizati
243	loss of localization to the cell membrane, significant loss of iodide transport activity but no effect on homodimerizati
471	no effect on localization to the cell membrane, iodide transport activity and homodimerization. significant loss of homo
525	loss of localization to the cell membrane, significant loss of iodide transport activity but no effect on homodimerizati

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-209968	Thyroxine biosynthesis
R-HSA-5619096	Defective SLC5A5 causes thyroid dyshormonogenesis 1 (TDH1)
R-HSA-9958790	SLC-mediated transport of inorganic anions
R-HSA-428643	Organic anion transport by SLC5/17/25 transporters
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-209776	Metabolism of amine-derived hormones
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport
R-HSA-5619102	SLC transporter disorders
R-HSA-5619115	Disorders of transmembrane transporters
R-HSA-71291	Metabolism of amino acids and derivatives

MSigDB gene sets: 206 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_162, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_RESPONSE_TO_KETONE, GOBP_RESPONSE_TO_CAMP

GO Biological Process (12): thyroid hormone generation (GO:0006590), monoatomic ion transport (GO:0006811), sodium ion transport (GO:0006814), iodide transport (GO:0015705), cellular response to cAMP (GO:0071320), cellular response to gonadotropin stimulus (GO:0071371), transport across blood-brain barrier (GO:0150104), iodide transmembrane transport (GO:1904200), cellular response to forskolin (GO:1904322), cellular response to Thyroid stimulating hormone (GO:1904401), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085)

GO Molecular Function (9): sodium:iodide symporter activity (GO:0008507), iodide transmembrane transporter activity (GO:0015111), monoatomic anion:sodium symporter activity (GO:0015373), protein homodimerization activity (GO:0042803), metal ion binding (GO:0046872), protein binding (GO:0005515), symporter activity (GO:0015293), solute:sodium symporter activity (GO:0015370), transmembrane transporter activity (GO:0022857)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), extracellular exosome (GO:0070062), extracellular vesicle (GO:1903561)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Metabolism of amine-derived hormones	1
SLC transporter disorders	1
SLC-mediated transmembrane transport	1
SLC-mediated transport of organic anions	1
Metabolism of amino acids and derivatives	1
Transport of small molecules	1
Disorders of transmembrane transporters	1
Disease	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
iodide transport	2
cellular anatomical structure	2
thyroid hormone metabolic process	1
metal ion transport	1
monoatomic anion transport	1
inorganic anion transport	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
cellular response to hormone stimulus	1
response to gonadotropin	1
vascular transport	1
monoatomic anion transmembrane transport	1
cellular response to lipid	1
cellular response to alcohol	1
cellular response to ketone	1
response to forskolin	1
response to Thyroid stimulating hormone	1
cellular response to glycoprotein	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
cellular process	1
iodide transmembrane transporter activity	1
monoatomic anion:sodium symporter activity	1
monoatomic anion transmembrane transporter activity	1
monoatomic anion:monoatomic cation symporter activity	1
solute:sodium symporter activity	1
identical protein binding	1
protein dimerization activity	1
cation binding	1
binding	1
secondary active transmembrane transporter activity	1
sodium ion transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
transporter activity	1
transmembrane transport	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1

Protein interactions and networks

STRING

1251 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC5A5	TG	P01266	970
SLC5A5	TSHR	P16473	947
SLC5A5	TPO	P07202	934
SLC5A5	SLC26A4	O43511	924
SLC5A5	IYD	Q6PHW0	917
SLC5A5	PAX8	Q06710	867
SLC5A5	DUOXA2	Q1HG44	851
SLC5A5	FOXE1	O00358	836
SLC5A5	NKX2-1	P43699	813
SLC5A5	DUOX2	Q9NRD8	794
SLC5A5	SLC2A1	P11166	738
SLC5A5	TPCN1	Q9ULQ1	727
SLC5A5	BRAF	P15056	683
SLC5A5	SLC16A2	P36021	682
SLC5A5	KCNE2	Q9Y6J6	639

IntAct

9 interactions, top by confidence:

A	B	Type	Score
NOTCH2NLC	SLC5A5	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	SLC5A5	psi-mi:“MI:0915”(physical association)	0.560
SLC5A5	SLC19A2	psi-mi:“MI:0914”(association)	0.530
SLC5A5	NOTCH2NLC	psi-mi:“MI:0915”(physical association)	0.000
SLC5A5	CYSRT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (46): ORMDL2 (Affinity Capture-MS), SFXN5 (Affinity Capture-MS), SLC19A2 (Affinity Capture-MS), VSIG8 (Affinity Capture-MS), TUBB3 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), CTU2 (Affinity Capture-MS), ARL5B (Affinity Capture-MS), YIPF3 (Affinity Capture-MS), SLC5A5 (Negative Genetic), SLC5A5 (Negative Genetic), SLC5A5 (Negative Genetic), SLC5A5 (Negative Genetic), SLC5A5 (Positive Genetic), CYSRT1 (Two-hybrid)

ESM2 similar proteins: A1L3M3, A7MBD8, A8I1B9, A8WHP3, B3TP03, B5D5N9, D3ZMM8, O08812, P11170, P13866, P18581, P30823, P30825, P52569, P53790, P53791, P70423, P83740, Q01650, Q09143, Q1EHB4, Q28I80, Q3ZC26, Q3ZMH1, Q49B93, Q5BL81, Q5PR34, Q5RAG7, Q63008, Q63016, Q6DCE8, Q7SYH5, Q7T384, Q7YQK4, Q8BGK6, Q8BYF6, Q8K0E3, Q8N695, Q8WWX8, Q8WY07

Diamond homologs: A7MBD8, O70247, P83740, Q1EHB4, Q3ZMH1, Q49B93, Q5BL81, Q5U4D8, Q63008, Q7SYH5, Q7T384, Q8BYF6, Q8N695, Q92911, Q99PN0, Q9XT77, Q9Y289, Q5E733

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
BRAF	“down-regulates quantity by repression”	SLC5A5	“transcriptional regulation”
PAX8	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
TSHB	“up-regulates quantity by stabilization”	SLC5A5
TSHB	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
SLC5A5	“up-regulates activity”	iodide	“chemical activation”
TGFB1	“down-regulates quantity by repression”	SLC5A5	“transcriptional regulation”
APEX1	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
CREB1	“up-regulates quantity by expression”	SLC5A5	“transcriptional regulation”
SLC5A5	“up-regulates quantity”	iodide	relocalization
SLC5A5	“up-regulates quantity”	sodium(1+)	relocalization
“Diisodecyl phthalate”	“up-regulates quantity by expression”	SLC5A5
“monobenzyl phthalate”	“up-regulates quantity by expression”	SLC5A5
“bis(2-ethylhexyl) phthalate”	“up-regulates quantity by expression”	SLC5A5

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	27
Likely pathogenic	28
Uncertain significance	126
Likely benign	331
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
2693903	NM_000453.3(SLC5A5):c.280C>T (p.Gln94Ter)	Pathogenic
2694996	NM_000453.3(SLC5A5):c.1590T>G (p.Tyr530Ter)	Pathogenic
2744488	NM_000453.3(SLC5A5):c.649del (p.Arg217fs)	Pathogenic
2744998	NM_000453.3(SLC5A5):c.22dup (p.Glu8fs)	Pathogenic
2754354	NM_000453.3(SLC5A5):c.1353_1363dup (p.Leu455fs)	Pathogenic
2767410	NM_000453.3(SLC5A5):c.1330-2A>G	Pathogenic
2797661	NM_000453.3(SLC5A5):c.166del (p.Ala56fs)	Pathogenic
2876043	NM_000453.3(SLC5A5):c.741dup (p.Val248fs)	Pathogenic
2884395	NM_000453.3(SLC5A5):c.451dup (p.Ala151fs)	Pathogenic
2973621	NM_000453.3(SLC5A5):c.652C>T (p.Gln218Ter)	Pathogenic
2982864	NM_000453.3(SLC5A5):c.1565del (p.Ser522fs)	Pathogenic
3242647	NC_000019.9:g.(?17999120)(17999284_?)del	Pathogenic
3242648	NC_000019.9:g.(?17984927)(17985032_?)del	Pathogenic
3242649	NC_000019.9:g.(?17991654)(17991782_?)del	Pathogenic
3242650	NC_000019.9:g.(?17991249)(17994856_?)del	Pathogenic
3242651	NC_000019.9:g.(?17992749)(17999284_?)del	Pathogenic
3242653	NC_000019.9:g.(?17985321)(17991512_?)del	Pathogenic
3645972	NM_000453.3(SLC5A5):c.492del (p.Trp165fs)	Pathogenic
4760216	NM_000453.3(SLC5A5):c.495G>A (p.Trp165Ter)	Pathogenic
7664	NM_000453.3(SLC5A5):c.1060A>C (p.Thr354Pro)	Pathogenic
7665	NM_000453.3(SLC5A5):c.816C>A (p.Cys272Ter)	Pathogenic
7667	NM_000453.3(SLC5A5):c.1593C>G (p.Tyr531Ter)	Pathogenic
7668	NM_000453.3(SLC5A5):c.277G>C (p.Gly93Arg)	Pathogenic
7669	NM_000453.3(SLC5A5):c.1628G>A (p.Gly543Glu)	Pathogenic
7671	NG_012930.1:g.7540_13728delins431	Pathogenic
983276	NM_000453.3(SLC5A5):c.152del (p.Gly51fs)	Pathogenic
983277	NM_000453.3(SLC5A5):c.1261G>A (p.Gly421Arg)	Pathogenic
2693188	NM_000453.3(SLC5A5):c.1243-1G>T	Likely pathogenic
2703263	NM_000453.3(SLC5A5):c.839+1G>A	Likely pathogenic
2729650	NM_000453.3(SLC5A5):c.1058+1G>A	Likely pathogenic

SpliceAI

2285 predictions. Top by Δscore:

Variant	Effect	Δscore
19:17874136:A:AG	acceptor_gain	1.0000
19:17874137:G:GA	acceptor_gain	1.0000
19:17874201:ACGGT:A	donor_loss	1.0000
19:17874202:CGG:C	donor_loss	1.0000
19:17874203:GGTGA:G	donor_loss	1.0000
19:17874204:G:A	donor_loss	1.0000
19:17874205:T:A	donor_loss	1.0000
19:17874206:GAGTG:G	donor_loss	1.0000
19:17874492:A:AG	acceptor_gain	1.0000
19:17874493:G:GG	acceptor_gain	1.0000
19:17874545:GGTG:G	donor_loss	1.0000
19:17874567:G:T	donor_gain	1.0000
19:17874660:A:AG	acceptor_gain	1.0000
19:17874660:ATAGT:A	acceptor_gain	1.0000
19:17874661:T:G	acceptor_gain	1.0000
19:17874661:TA:T	acceptor_loss	1.0000
19:17874662:A:AG	acceptor_gain	1.0000
19:17874662:AGT:A	acceptor_gain	1.0000
19:17874663:G:GA	acceptor_gain	1.0000
19:17874663:GT:G	acceptor_gain	1.0000
19:17874663:GTG:G	acceptor_gain	1.0000
19:17874729:GTG:G	donor_gain	1.0000
19:17874732:G:GA	donor_loss	1.0000
19:17874732:G:GG	donor_gain	1.0000
19:17874733:T:A	donor_loss	1.0000
19:17875943:AT:A	acceptor_gain	1.0000
19:17875944:T:G	acceptor_gain	1.0000
19:17875944:T:TA	acceptor_gain	1.0000
19:17875950:AG:A	acceptor_gain	1.0000
19:17875951:GG:G	acceptor_gain	1.0000

AlphaMissense

4083 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:17872515:A:C	S66R	1.000
19:17872517:C:A	S66R	1.000
19:17872517:C:G	S66R	1.000
19:17872507:T:C	L63P	0.999
19:17872513:C:A	A65D	0.999
19:17872516:G:T	S66I	0.999
19:17872518:T:C	F67L	0.999
19:17872520:C:A	F67L	0.999
19:17872520:C:G	F67L	0.999
19:17872528:C:A	A70D	0.999
19:17874506:G:C	G146R	0.999
19:17874528:C:A	A153D	0.999
19:17874713:C:G	C175W	0.999
19:17880935:C:A	A347D	0.999
19:17880940:A:C	S349R	0.999
19:17880942:T:A	S349R	0.999
19:17880942:T:G	S349R	0.999
19:17880944:G:A	G350D	0.999
19:17880950:T:C	L352P	0.999
19:17880952:A:C	S353R	0.999
19:17881960:C:A	S353R	0.999
19:17881960:C:G	S353R	0.999
19:17881962:C:T	T354I	0.999
19:17881973:A:C	S358R	0.999
19:17881975:C:A	S358R	0.999
19:17881975:C:G	S358R	0.999
19:17882161:G:A	G395E	0.999
19:17872411:G:A	G31E	0.998
19:17872497:G:C	G60R	0.998
19:17872498:G:A	G60D	0.998

dbSNP variants (sampled 300 via entrez): RS1000171906 (19:17870308 C>G), RS1000434039 (19:17890825 T>A,C), RS1000543077 (19:17894287 G>A,T), RS1000581818 (19:17876947 C>T), RS1000900048 (19:17871065 A>G), RS1000942032 (19:17895135 C>A), RS1000991697 (19:17888558 A>C,G), RS1001011392 (19:17876673 C>A,T), RS1001116271 (19:17891691 T>A), RS1001175251 (19:17891459 G>A,T), RS1001424034 (19:17874466 G>A), RS1001533845 (19:17877416 T>C), RS1001559859 (19:17877735 C>T), RS1001673194 (19:17871915 C>T), RS1001869341 (19:17876182 C>A)

Disease associations

OMIM: gene MIM:601843 | disease phenotypes: MIM:274400

GenCC curated gene-disease

Disease	Classification	Inheritance
thyroid dyshormonogenesis 1	Definitive	Autosomal recessive
familial thyroid dyshormonogenesis	Supportive	Autosomal recessive

Mondo (3): thyroid dyshormonogenesis 1 (MONDO:0020716), congenital hypothyroidism (MONDO:0018612), familial thyroid dyshormonogenesis (MONDO:0010132)

Orphanet (2): Familial thyroid dyshormonogenesis (Orphanet:95716), Congenital hypothyroidism (Orphanet:442)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000158	Macroglossia
HP:0000270	Delayed cranial suture closure
HP:0000282	Facial edema
HP:0000407	Sensorineural hearing impairment
HP:0000821	Hypothyroidism
HP:0000851	Congenital hypothyroidism
HP:0000853	Goiter
HP:0000958	Dry skin
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001254	Lethargy
HP:0001265	Hyporeflexia
HP:0001510	Growth delay
HP:0001537	Umbilical hernia
HP:0001662	Bradycardia
HP:0002019	Constipation
HP:0002045	Hypothermia
HP:0002925	Elevated circulating thyroid-stimulating hormone concentration
HP:0003265	Neonatal hyperbilirubinemia
HP:0004491	Large posterior fontanelle
HP:0005280	Depressed nasal bridge
HP:0005930	Abnormal epiphysis morphology
HP:0006579	Prolonged neonatal jaundice
HP:0008263	Thyroid defect in oxidation and organification of iodide
HP:0008828	Delayed proximal femoral epiphyseal ossification
HP:0008872	Feeding difficulties in infancy
HP:0011437	Maternal autoimmune disease
HP:0012758	Neurodevelopmental delay
HP:0025482	Positive perchlorate discharge test

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005169_5	Diastolic blood pressure	7.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D003409	Congenital Hypothyroidism	C05.116.099.343.347; C05.116.132.256; C16.320.240.625; C19.297.155; C19.874.482.281
C564766	Thyroid Dyshormonogenesis 1 (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 iodide symporter, sodium-dependent multivitamin transporter and sodium-coupled monocarboxylate transporters

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tretinoin	decreases reaction, increases activity, decreases expression, affects cotreatment, affects localization (+2 more)	9
Sodium Iodide	decreases reaction, increases abundance, decreases export, increases reaction, increases uptake	8
perchlorate	decreases reaction, increases reaction, increases uptake, increases abundance	6
Iodides	decreases reaction, increases uptake, increases reaction	6
sodium perchlorate	increases uptake, decreases reaction	5
potassium perchlorate	decreases reaction, increases uptake	4
Iodine	affects transport, decreases reaction, increases uptake, affects cotreatment, increases expression	4
Sodium Pertechnetate Tc 99m	decreases reaction, increases uptake, increases reaction	4
Dibutyl Phthalate	decreases reaction, increases uptake, decreases expression	3
triclocarban	decreases reaction, increases uptake	2
perrhenate	decreases reaction, increases uptake	2
sodium thiocyanate	decreases reaction, increases uptake	2
thiocyanate	affects transport, decreases reaction, increases uptake	2
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases expression, decreases reaction, increases expression, increases reaction	2
etoxazole	increases uptake, decreases reaction	2
Resveratrol	decreases reaction, increases expression	2
Decitabine	affects cotreatment, increases expression, increases uptake	2
Troglitazone	affects cotreatment, increases expression	2
Azacitidine	affects cotreatment, affects expression, increases expression	2
Butyrates	affects cotreatment, affects expression, increases expression, increases uptake	2
Dexamethasone	affects cotreatment, increases expression, increases reaction, increases uptake, increases activity	2
Colforsin	increases activity, increases expression, affects cotreatment, decreases reaction	2
Tobacco Smoke Pollution	affects expression	2
triphenyl phosphate	decreases reaction, increases uptake	1
captax	decreases reaction, increases uptake	1
bisphenol A	increases uptake, decreases reaction	1
polymarcine	decreases reaction, increases uptake	1
di-n-octyl phthalate	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
trichostatin A	increases expression	1

Cellosaurus cell lines

25 cell lines: 24 cancer cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_6019	SK-Hep-1-NIS	Cancer cell line	Male
CVCL_C6U6	WAe009-A-93	Embryonic stem cell	Female
CVCL_D5KB	B16F10-Fluc-hNIS	Cancer cell line	Male
CVCL_E8E8	HeLa-HA-hNIS	Cancer cell line	Female
CVCL_F1MW	HyCyte B-CPAP KO-hSLC5A5	Cancer cell line	Female
CVCL_QZ69	A375-Fluc-Neo/hNIS-Puro	Cancer cell line	Female
CVCL_QZ71	A375-hNIS-Neo/eGFP-Puro	Cancer cell line	Female
CVCL_QZ72	A375-hNIS-Puro	Cancer cell line	Female
CVCL_QZ75	A375-iRFP-Neo/hNIS-Puro	Cancer cell line	Female
CVCL_QZ80	A549-hNIS-Neo	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05228184	PHASE4	TERMINATED	Use of Tirosint®-SOL or Tablet Formulations of Levothyroxine in Pediatric Patients With Congenital Hypothyroidism (CH)
NCT05371262	PHASE4	COMPLETED	Influence of Initial Levothyroxine Dose on Neurodevelopmental and Growth Outcomes in Congenital Hypothyroidism
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT00403390	Not specified	COMPLETED	Generic vs. Name-Brand Levothyroxine
NCT00493103	Not specified	COMPLETED	TG Gene Mutations and Congenital Hypothyroidism
NCT00497575	Not specified	COMPLETED	Diagnosis and Follow-up of Patients With Subclinical Hypothyroidism
NCT00505479	Not specified	UNKNOWN	Iodine Status in Pregnant Women and Their Newborns: is Congenital Hypothyroidism Related to Iodine Deficiency in Pregnancy?
NCT01223638	Not specified	WITHDRAWN	The Prevalence of Hearing Loss Among Children With Congenital Hypothyroidism
NCT01349634	Not specified	COMPLETED	The Effects of Iodized Salt on Cognitive Development in Ethiopia
NCT01488721	Not specified	COMPLETED	Clinical Evaluation of NeoPlex4 Assay and NeoPlex System
NCT01916018	Not specified	COMPLETED	Clinical and Genetic Analysis in Congenital Hypothyroidism Due to Thyroid Dysgenesis.
NCT02307175	Not specified	COMPLETED	A Study of 99m Tc Pertechnetate Produced in High Energy Cyclotron in Patients With Thyroid Scan Indication
NCT02374593	Not specified	COMPLETED	Targeted Levothyroxine Dosing in Infants With Congenital Hypothyroidism
NCT04712760	Not specified	UNKNOWN	Congenital Hypothyroidism in Children With Eutopic Gland or Thyroid Hemiagenesis: Predictive Factors for Transient vs Permanent Hypothyroidism.
NCT04734457	Not specified	UNKNOWN	Final Height in Patients With CH Diagnosed by the Screening
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06724224	Not specified	RECRUITING	Comparison of Levothyroxine Formulations in the Treatment of Congenital Hypothyroidism
NCT06728735	Not specified	RECRUITING	Role of Next Generation Sequencing in the Etiological Diagnosis of Permanent Congenital Hypothyroidism With in Situ Thyroid
NCT06864039	Not specified	ENROLLING_BY_INVITATION	Quality of Life and Long-term Outcome of Adequately Treated Congenital Hypothyroidism
NCT06864351	Not specified	RECRUITING	Prospective Evaluation of OptiThyDose
NCT07126353	Not specified	NOT_YET_RECRUITING	Metabolic Risk Assessment in Prepubertal Children With Congenital Hypothyroidism
NCT07280104	Not specified	RECRUITING	Infants With Primary Congenital Hypothyroidism and Development
NCT07425028	Not specified	NOT_YET_RECRUITING	Evaluation of an Intensified Systematic Screening for Congenital Hypothyroidism in Premature Newborns
NCT07579988	Not specified	NOT_YET_RECRUITING	Ultrasound Measurement of Thyroid Volume in Term Newborns