SLC16A2

Summary

SLC16A2 (solute carrier family 16 member 2, HGNC:10923) is a protein-coding gene on chromosome Xq13.2, encoding Monocarboxylate transporter 8 (P36021). Specific thyroid hormone transmembrane transporter, that mediates both uptake and efflux of thyroid hormones across the cell membrane independently of pH or a Na(+) gradient. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes an integral membrane protein that functions as a transporter of thyroid hormone. The encoded protein facilitates the cellular importation of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine (T2). This gene is expressed in many tissues and likely plays an important role in the development of the central nervous system. Loss of function mutations in this gene are associated with psychomotor retardation in males while females exhibit no neurological defects and more moderate thyroid-deficient phenotypes. This gene is subject to X-chromosome inactivation. Mutations in this gene are the cause of Allan-Herndon-Dudley syndrome.

Source: NCBI Gene 6567 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Allan-Herndon-Dudley syndrome (Definitive, ClinGen)
• Clinical variants (ClinVar): 490 total — 71 pathogenic, 37 likely-pathogenic
• Phenotypes (HPO): 79
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_006517

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10923
Approved symbol	SLC16A2
Name	solute carrier family 16 member 2
Location	Xq13.2
Locus type	gene with protein product
Status	Approved
Aliases	XPCT, MCT8, MCT7, DXS128E
Ensembl gene	ENSG00000147100
Ensembl biotype	protein_coding
OMIM	300095
Entrez	6567

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 nonsense_mediated_decay

ENST00000587091, ENST00000590447, ENST00000636771, ENST00000878588, ENST00000878589, ENST00000878590, ENST00000878591, ENST00000878592, ENST00000878593, ENST00000922843, ENST00000922844, ENST00000922845, ENST00000922846, ENST00000922847, ENST00000961799

RefSeq mRNA: 1 — MANE Select: NM_006517 NM_006517

CCDS: CCDS14426

Canonical transcript exons

ENST00000587091 — 6 exons

Exon	Start	End
ENSE00000978746	74520990	74521134
ENSE00001154251	74531333	74533916
ENSE00001159895	74529213	74529441
ENSE00001159902	74525750	74525893
ENSE00001159907	74524359	74524809
ENSE00002909129	74421493	74422067

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 92.25.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.7823 / max 102.4592, expressed in 1262 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196757	8.5123	1257
196758	0.2700	154

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right adrenal gland	UBERON:0001233	92.25	gold quality
right adrenal gland cortex	UBERON:0035827	92.10	gold quality
right lobe of liver	UBERON:0001114	91.93	gold quality
left adrenal gland	UBERON:0001234	91.69	gold quality
left adrenal gland cortex	UBERON:0035825	91.60	gold quality
adrenal cortex	UBERON:0001235	90.61	gold quality
cortical plate	UBERON:0005343	90.39	gold quality
adrenal gland	UBERON:0002369	90.16	gold quality
adrenal tissue	UBERON:0018303	88.88	gold quality
liver	UBERON:0002107	88.29	gold quality
ganglionic eminence	UBERON:0004023	88.19	gold quality
ventricular zone	UBERON:0003053	85.95	gold quality
adenohypophysis	UBERON:0002196	85.22	gold quality
stromal cell of endometrium	CL:0002255	85.10	gold quality
gall bladder	UBERON:0002110	84.33	gold quality
right ovary	UBERON:0002118	84.14	gold quality
left ovary	UBERON:0002119	83.96	gold quality
right coronary artery	UBERON:0001625	83.76	gold quality
pituitary gland	UBERON:0000007	83.55	gold quality
right atrium auricular region	UBERON:0006631	83.09	gold quality
left uterine tube	UBERON:0001303	82.69	gold quality
body of uterus	UBERON:0009853	82.31	gold quality
right lobe of thyroid gland	UBERON:0001119	82.03	gold quality
left lobe of thyroid gland	UBERON:0001120	81.93	gold quality
cardiac atrium	UBERON:0002081	81.89	gold quality
thyroid gland	UBERON:0002046	81.88	gold quality
mucosa of stomach	UBERON:0001199	81.68	gold quality
left coronary artery	UBERON:0001626	81.39	gold quality
coronary artery	UBERON:0001621	81.32	gold quality
apex of heart	UBERON:0002098	81.12	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.08

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ZNF395

miRNA regulators (miRDB)

134 targeting SLC16A2, 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-4481	100.00	66.42	1669
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-221-5P	99.86	65.45	1052

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Association between mutations in MCT8, a thyroid hormone transporter, and severe X-linked psychomotor retardation (PMID:15488219)
• MCT8 plays an important role for proper central nervous system development by transporting TH into neurons as its main target cells. (PMID:15661862)
• X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene. (PMID:15834651)
• Abnormal transporter function is reflected in elevated free triiodothyronine and lowered free thyroxine levels in the blood. Infancy and childhood in the Allan-Herndon-Dudley syndrome are marked by hypotonia, weakness, reduced (PMID:15889350)
• hMCT8 mediates plasma membrane transport of iodothyronines, thus increasing their intracellular availability. (PMID:16887882)
• The SLC16A2 (formerly MCT8) gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe, X-linked, psychomotor retardation and high serum T3 levels. (PMID:16957765)
• findings support the hypothesis that the severe psychomotor retardation and elevated serum T3 hormone levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons (PMID:17356046)
• MCT8 plays an important role in the development of the central nervous system by transporting thyroid hormone into neurons as its main target cells. (Review) (PMID:17684393)
• Mutants L434W, L568P, and S194F showed significant residual transport capacity, which may underlie the more advanced psychomotor development observed in patients with these mutations. (PMID:18187543)
• MCT10 is at least as active a thyroid hormone transporter as hMCT8, and that both transporters facilitate iodothyronine uptake as well as efflux. (PMID:18337592)
• Allan-Herndon-Dudley syndrome clinical features can be present in female MCT8 mutation carriers whenever there is unfavorable nonrandom X-inactivation. (PMID:18398436)
• abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular 3,3’,5-triiodothyronine concentrations. (PMID:18636565)
• Data report that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human. (PMID:18687783)
• The S107P single nucleotide polymorphism in SLC16A2, the gene encoding the thyroid hormone (TH)-specific transporter monocarboxylate transporter 8 (MCT8), is frequent in the male population in Galicia. (PMID:18710470)
• Data show that small interfering RNA depletion of endogenous MCT8 resulted in increased cell survival and decreased T(3) uptake. (PMID:19022891)
• Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects. (PMID:19194886)
• In prolonged critically ill patients, authors measured increased MCT8 but not MCT10 gene expression levels in liver and skeletal muscle as compared with patients undergoing acute surgical stress. (PMID:19439506)
• lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the neurodevelopmental phenotype in MCT8-deficiencies; Mct8-deficient mouse neurons are functionally complemented by other transporters (PMID:19641107)
• The finding that the cell type determines surface expression and T(3) transport activities of missense mutants in MCT8 may be important to understand phenotypic variability among carriers of different mutations. (PMID:19648159)
• MCT8 exists as monomer and homodimer in transiently and stably transfected cells. (PMID:19797118)
• Data show that SLC16A2 involvement should be considered in males with learning disability, an associated motor or movement disorder, and evidence of delayed myelination on brain MRI. (PMID:19811520)
• Increased MCT8 and decreased MCT10 expression within placentae of pregnancies complicated by IUGR may contribute to aberrant development of the fetoplacental unit. (PMID:20167367)
• Thigh subcutaneous adipose tissue from subjects with familial partial lipodystrophy 2 has lower expression of MCT8 and activity than abdominal SAT, suggesting that changes in local thyroid hormone metabolism may occur in areas with lipoatrophy. (PMID:20373986)
• structural model and functional data (PMID:20628049)
• Increased monocarboxylate transporter 8 expression and intracellular T(3) accumulation may contribute to the altered T(3) responsiveness of IUGR cytotrophoblasts. (PMID:20660035)
• findings demonstrate a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS (PMID:20705735)
• Group-by-genotype interactions for 2 highly correlated SNPs (rs496549 & rs479640) revealed co-localised association clusters in the left occipital cortex. (PMID:21208750)
• monocarboxylate transporter 8 facilitates bromoacetyl [(125)I] iodothyronine transport, but is not labeled by it (PMID:21315799)
• nonsense mutation in MCT8 (c.1102A–>T (p.R368X)) was identified in the proband causing X-linked leucoencephalopathy (PMID:21415082)
• From the early first trimester, immunohistochemistry localised MCT8 to the microvasculature and to undifferentiated CNS cells in the cerebral cortex. However, human NT2 cell neurodifferentiation is not dependent upon triiodothyronine or MCT8. (PMID:21486766)
• Our results implicate peripheral deiodination in the peculiar hormonal constellation of MCT8-deficient patients (PMID:21813593)
• 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxysmal extrapyramidal symptoms. In one subject a novel mutation is described. (PMID:22805248)
• This study indicates that MCT8 mutations are a relatively frequent cause of X-linked mental retardation. (PMID:22924588)
• study reports a family with two patients affected by Allan-Herndon-Dudley syndrome in two consecutive generations with a c.670 G->A, p.A224 mutation in the MCT8 gene (PMID:23419639)
• Importance of cysteine residues in the thyroid hormone transporter MCT8. (PMID:23546606)
• MCT8 mutations in Allan-Herndon-Dudley Syndrome patients may have tissue-specific effects on thyroid hormone transport. (PMID:23550058)
• We describe three new SLC16A2 mutations associated with different levels of clinical severity in patients with psychomotor retardation disorders. (PMID:23568789)
• Results indicate that His192 is sensitive to modification by DEPC and may be located close to a putative substrate recognition site within the MCT8 protein, important for efficient TH uptake. (PMID:23610131)
• A boy with Allan-Herndon-Dudley syndrome and his heterozygous mother had a point mutation in exon 3 of the MCT8 gene 1201G>A:G401R which changes the properties of the protein. (PMID:23744248)
• Monocarboxylate transporter 8 modulates the viability and invasive capacity of human placental cells and fetoplacental growth in mice. (PMID:23776477)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc16a2	ENSDARG00000098694
mus_musculus	Slc16a2	ENSMUSG00000033965
rattus_norvegicus	Slc16a2	ENSRNOG00000002832
drosophila_melanogaster	Mct1	FBGN0023549
drosophila_melanogaster	CG14196	FBGN0031002
drosophila_melanogaster	CG8051	FBGN0031012
drosophila_melanogaster	Sln	FBGN0033657
drosophila_melanogaster	CG8468	FBGN0033913
drosophila_melanogaster	Targ	FBGN0033955
drosophila_melanogaster	CG13907	FBGN0035173
drosophila_melanogaster	out	FBGN0259834
caenorhabditis_elegans		WBGENE00003986
caenorhabditis_elegans		WBGENE00010834
caenorhabditis_elegans		WBGENE00015273
caenorhabditis_elegans		WBGENE00015676
caenorhabditis_elegans		WBGENE00020168
caenorhabditis_elegans		WBGENE00021227

Paralogs (13): SLC16A8 (ENSG00000100156), SLC16A6 (ENSG00000108932), SLC16A10 (ENSG00000112394), SLC16A7 (ENSG00000118596), SLC16A3 (ENSG00000141526), SLC16A12 (ENSG00000152779), SLC16A1 (ENSG00000155380), SLC16A14 (ENSG00000163053), SLC16A9 (ENSG00000165449), SLC16A4 (ENSG00000168679), SLC16A5 (ENSG00000170190), SLC16A11 (ENSG00000174326), SLC16A13 (ENSG00000174327)

Protein

Protein identifiers

Monocarboxylate transporter 8 — P36021 (reviewed: P36021)

Alternative names: Monocarboxylate transporter 7, Solute carrier family 16 member 2, X-linked PEST-containing transporter

All UniProt accessions (3): P36021, A0A1B0GVB4, K7ELT4

UniProt curated annotations — full annotation on UniProt →

Function. Specific thyroid hormone transmembrane transporter, that mediates both uptake and efflux of thyroid hormones across the cell membrane independently of pH or a Na(+) gradient. Major substrates are the iodothyronines T3 and T4 and to a lesser extent rT3 and 3,3-diiodothyronine (3,3’-T2). Acts as an important mediator of thyroid hormone transport, especially T3, through the blood-brain barrier.

Subunit / interactions. Monomer. Homodimer. Homooligomer.

Subcellular location. Cell membrane. Apical cell membrane.

Tissue specificity. Highly expressed in liver and heart. In adult brain tissue expression is largely confined to endothelial cells of the blood-brain barrier (at protein level).

Disease relevance. Monocarboxylate transporter 8 deficiency (MCT8 deficiency) [MIM:300523] Consists of a severe form of X-linked psychomotor retardation combined with abnormal thyroid hormone (TH) levels. Thyroid hormone deficiency can be caused by defects of hormone synthesis and action, but it has also been linked to a defect in cellular hormone transport. Affected patients are males with abnormal relative concentrations of three circulating iodothyronines, as well as severe neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. Abnormal brain development associated with MCT8 deficiency may be the consequence of either decreased or increased intracellular T3 concentrations.

Similarity. Belongs to the major facilitator superfamily. Monocarboxylate porter (TC 2.A.1.13) family.

RefSeq proteins (1): NP_006508* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011701	MFS	Family
IPR020846	MFS_dom	Domain
IPR036259	MFS_trans_sf	Homologous_superfamily
IPR050327	Proton-linked_MCT	Family

Pfam: PF07690

Catalyzed reactions (Rhea), 4 shown:

• 3,3’,5-triiodo-L-thyronine(out) = 3,3’,5-triiodo-L-thyronine(in) (RHEA:71811)
• 3,3’,5’-triiodo-L-thyronine(out) = 3,3’,5’-triiodo-L-thyronine(in) (RHEA:71815)
• L-thyroxine(out) = L-thyroxine(in) (RHEA:71819)
• 3,3’-diiodo-L-thyronine(out) = 3,3’-diiodo-L-thyronine(in) (RHEA:71823)

UniProt features (64 total): sequence variant 23, topological domain 13, transmembrane region 12, mutagenesis site 8, compositionally biased region 3, region of interest 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
9DWY	ELECTRON MICROSCOPY	2.9
9FOT	ELECTRON MICROSCOPY	3
8ZKN	ELECTRON MICROSCOPY	3.06
8ZKO	ELECTRON MICROSCOPY	3.13
9FKN	ELECTRON MICROSCOPY	3.4
9GF8	ELECTRON MICROSCOPY	3.5
9GV5	ELECTRON MICROSCOPY	4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36021-F1	79.48	0.49

Antibody-complex structures (SAbDab): 2 — 9FKN, 9GF8

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 (1): 2

Mutagenesis-validated functional residues (8):

Position	Phenotype
118	reduction of thyroid hormone (th) transport.
118	does not alter kinetic characteristics of thyroid hormone (th) transport.
186	no effect on thyroid hormone (th) transport.
216	no effect on thyroid hormone transport. no effect on protein abundance. no effect on protein localization to the plasma
371	does not affect localization to the cell membrane. abolishes t3 uptake activity.
376	no effect on thyroid hormone (th) transport.
424	does not affect localization to the cell membrane. abolishes t3 uptake activity.
490	no effect on thyroid hormone (th) transport.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-879518	Organic anion transport by SLCO transporters
R-HSA-382551	Transport of small molecules
R-HSA-425397	Transport of vitamins, nucleosides, and related molecules
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 341 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, E2F_Q4_01, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_162, MODULE_64, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GGGTGGRR_PAX4_03, GOBP_CELL_CELL_SIGNALING, GOBP_ORGANIC_ACID_TRANSPORT, GOBP_NEURAL_PRECURSOR_CELL_PROLIFERATION, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, MODULE_368

GO Biological Process (11): amino acid metabolic process (GO:0006520), thyroid hormone generation (GO:0006590), monocarboxylic acid transport (GO:0015718), thyroid hormone metabolic process (GO:0042403), thyroid hormone transport (GO:0070327), thyroid-stimulating hormone secretion (GO:0070460), amino acid import across plasma membrane (GO:0089718), transport across blood-brain barrier (GO:0150104), negative regulation of neural precursor cell proliferation (GO:2000178), transmembrane transport (GO:0055085), carboxylic acid transmembrane transport (GO:1905039)

GO Molecular Function (7): monocarboxylic acid transmembrane transporter activity (GO:0008028), amino acid transmembrane transporter activity (GO:0015171), thyroid hormone transmembrane transporter activity (GO:0015349), identical protein binding (GO:0042802), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857), carboxylic acid transmembrane transporter activity (GO:0046943)

GO Cellular Component (3): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
SLC-mediated transport of organic anions	1
SLC-mediated transmembrane transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
carboxylic acid transport	2
amino acid transmembrane transport	2
transmembrane transport	2
transmembrane transporter activity	2
primary metabolic process	1
thyroid hormone metabolic process	1
modified amino acid metabolic process	1
phenol-containing compound metabolic process	1
hormone metabolic process	1
hormone transport	1
peptide hormone secretion	1
import across plasma membrane	1
vascular transport	1
negative regulation of cell population proliferation	1
neural precursor cell proliferation	1
regulation of neural precursor cell proliferation	1
transport	1
cellular process	1
monocarboxylic acid transport	1
carboxylic acid transmembrane transporter activity	1
secondary active transmembrane transporter activity	1
thyroid hormone transport	1
protein binding	1
binding	1
transporter activity	1
carboxylic acid transmembrane transport	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC16A2	SLCO1C1	Q9NYB5	980
SLC16A2	DIO2	Q92813	894
SLC16A2	SLC7A8	Q9UHI5	839
SLC16A2	DIO3	P55073	836
SLC16A2	TRH	P20396	787
SLC16A2	SLCO1A2	P46721	723
SLC16A2	RPS4Y1	P22090	718
SLC16A2	SLC5A5	Q92911	682
SLC16A2	THRB	P10828	680
SLC16A2	THRA	P10827	670
SLC16A2	RPS4X	P12631	659
SLC16A2	IL1RAPL1	Q9NZN1	646
SLC16A2	TSHB	P01222	603
SLC16A2	TSHR	P16473	601
SLC16A2	SLCO4A1	Q96BD0	596

IntAct

10 interactions, top by confidence:

A	B	Type	Score
CD9	ADAM10	psi-mi:“MI:0914”(association)	0.750
SLC16A2	FAM234A	psi-mi:“MI:0915”(physical association)	0.560
TEX29	TOR1A	psi-mi:“MI:0914”(association)	0.530
NT5E	SCAMP1	psi-mi:“MI:0914”(association)	0.530
NT5E	SCAMP3	psi-mi:“MI:0914”(association)	0.350
SLC16A2	QNG1	psi-mi:“MI:0914”(association)	0.350
SLC16A2	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350

BioGRID (64): SLC16A2 (Affinity Capture-MS), SLC16A2 (Affinity Capture-MS), SLC16A2 (Affinity Capture-MS), SLC16A2 (Affinity Capture-MS), SLC16A2 (Affinity Capture-MS), SLC16A2 (Affinity Capture-MS), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid), SLC16A2 (Two-hybrid)

ESM2 similar proteins: A1L1W9, A1L272, A2SWM2, A8WGF7, D3Z5L6, D4A9K4, F4IKF6, G5E8K6, G8XYX6, O15374, O35440, O70324, O70451, O70594, P30638, P36021, P53985, P53986, P53987, P53988, P57057, P58355, Q00910, Q03064, Q0VA82, Q3MHW6, Q3U9N9, Q569T7, Q5M7K3, Q5U3U7, Q5XGK0, Q63344, Q640L2, Q6DCX5, Q6GPQ3, Q6NMN6, Q6NT16, Q6NUB3, Q7ZWG6, Q8AVC3

Diamond homologs: A1L1W9, G8XYX6, O15374, O70324, P36021, Q3U9N9, Q7RTX9, Q8K1P8, Q8R0M8, Q8TF71, Q91Y77, M0RCI4, P36032, Q7TM99, A0A2U8U2M7, G5E8K6, O15375, O35440, O70451, P53988, Q17QR6, Q5R5M4, Q5ZJU0, Q63344, Q66HE2, Q7RTY0, Q7RTY1, Q8CE94, Q8K1C7, O15427, O60669, B0XWL0, B8N0F1, P57787, S0ECK8, A0LNN5

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
SLC16A2	“down-regulates quantity”	3,3’,5’-triiodothyronine	relocalization
SLC16A2	“down-regulates quantity”	L-thyroxine	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	71
Likely pathogenic	37
Uncertain significance	177
Likely benign	92
Benign	23

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1031649	NM_006517.5(SLC16A2):c.1070G>A (p.Trp357Ter)	Pathogenic
1031650	NM_006517.5(SLC16A2):c.972G>A (p.Trp324Ter)	Pathogenic
1077180	NM_006517.5(SLC16A2):c.-6_430+5del	Pathogenic
11632	NM_006517.5(SLC16A2):c.1313T>C (p.Leu438Pro)	Pathogenic
11633	NM_006517.5(SLC16A2):c.993del (p.Ala332fs)	Pathogenic
11636	NM_006517.5(SLC16A2):c.1190T>C (p.Leu397Pro)	Pathogenic
11637	NG_011641.2:g.(108110_108560)_(109645_112963)del	Pathogenic
11638	NM_006517.5(SLC16A2):c.1481T>C (p.Leu494Pro)	Pathogenic
11639	NM_006517.5(SLC16A2):c.1079T>G (p.Leu360Trp)	Pathogenic
11640	NM_006517.5(SLC16A2):c.1121C>A (p.Ser374Ter)	Pathogenic
11642	NM_006517.5(SLC16A2):c.1613del (p.Pro538fs)	Pathogenic
1327916	NM_006517.5(SLC16A2):c.852_862dup (p.Gln288fs)	Pathogenic
1335975	NM_006517.5(SLC16A2):c.850del (p.Leu284fs)	Pathogenic
1344896	NM_006517.5(SLC16A2):c.431-2A>G	Pathogenic
1369051	NM_006517.5(SLC16A2):c.99_100del (p.Glu34fs)	Pathogenic
1453369	NM_006517.5(SLC16A2):c.1193G>A (p.Gly398Asp)	Pathogenic
159900	NM_006517.5(SLC16A2):c.916C>T (p.Gln306Ter)	Pathogenic
159906	NM_006517.5(SLC16A2):c.277C>T (p.Gln93Ter)	Pathogenic
1686195	NM_006517.5(SLC16A2):c.407del (p.Asn136fs)	Pathogenic
1711189	NM_006517.5(SLC16A2):c.640C>T (p.Gln214Ter)	Pathogenic
1792385	NM_006517.5(SLC16A2):c.28G>T (p.Glu10Ter)	Pathogenic
193349	NM_006517.5(SLC16A2):c.326G>A (p.Trp109Ter)	Pathogenic
2010686	NM_006517.5(SLC16A2):c.1565del (p.Pro522fs)	Pathogenic
2024767	NM_006517.5(SLC16A2):c.2T>G (p.Met1Arg)	Pathogenic
2118223	NM_006517.5(SLC16A2):c.64C>T (p.Gln22Ter)	Pathogenic
212186	NM_006517.5(SLC16A2):c.940C>T (p.Arg314Ter)	Pathogenic
212188	NM_006517.5(SLC16A2):c.1392dup (p.Ile465fs)	Pathogenic
212189	NM_006517.5(SLC16A2):c.1474_1481del (p.Val492fs)	Pathogenic
212191	NM_006517.5(SLC16A2):c.256del (p.Arg86fs)	Pathogenic
212192	NM_006517.5(SLC16A2):c.374del (p.Tyr125fs)	Pathogenic

SpliceAI

1543 predictions. Top by Δscore:

Variant	Effect	Δscore
X:74422064:GCAG:G	donor_gain	1.0000
X:74520988:A:AG	acceptor_gain	1.0000
X:74520989:G:GG	acceptor_gain	1.0000
X:74521130:ACCAG:A	donor_loss	1.0000
X:74521132:CAGG:C	donor_loss	1.0000
X:74521133:AGGTA:A	donor_loss	1.0000
X:74521136:T:A	donor_loss	1.0000
X:74522903:GGCCC:G	donor_gain	1.0000
X:74524496:G:GT	donor_gain	1.0000
X:74525890:GCAG:G	donor_gain	1.0000
X:74525892:AGGT:A	donor_loss	1.0000
X:74525894:GT:G	donor_loss	1.0000
X:74525895:T:G	donor_loss	1.0000
X:74529207:CTCCA:C	acceptor_loss	1.0000
X:74529208:TCCAG:T	acceptor_loss	1.0000
X:74529209:CCAGG:C	acceptor_loss	1.0000
X:74529210:CAGGT:C	acceptor_loss	1.0000
X:74529211:A:AG	acceptor_gain	1.0000
X:74529211:A:T	acceptor_loss	1.0000
X:74529212:G:GG	acceptor_gain	1.0000
X:74529212:G:T	acceptor_loss	1.0000
X:74529212:GGTC:G	acceptor_gain	1.0000
X:74529212:GGTCC:G	acceptor_gain	1.0000
X:74531327:TTTCA:T	acceptor_loss	1.0000
X:74531328:TTCAG:T	acceptor_loss	1.0000
X:74531329:TCAGG:T	acceptor_loss	1.0000
X:74531330:CAGGC:C	acceptor_loss	1.0000
X:74531331:A:AG	acceptor_gain	1.0000
X:74531331:AGG:A	acceptor_loss	1.0000
X:74531332:G:GA	acceptor_gain	1.0000

AlphaMissense

3531 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:74524453:T:C	F224L	1.000
X:74524455:T:A	F224L	1.000
X:74524455:T:G	F224L	1.000
X:74521043:A:C	S162R	0.999
X:74521045:T:A	S162R	0.999
X:74521045:T:G	S162R	0.999
X:74521121:A:C	S188R	0.999
X:74521123:C:A	S188R	0.999
X:74521123:C:G	S188R	0.999
X:74524453:T:A	F224I	0.999
X:74524454:T:C	F224S	0.999
X:74524753:T:A	W324R	0.999
X:74524753:T:C	W324R	0.999
X:74529355:T:C	L438P	0.999
X:74421962:T:A	W109R	0.998
X:74421962:T:C	W109R	0.998
X:74421972:G:A	G112D	0.998
X:74521088:G:A	G177R	0.998
X:74521088:G:C	G177R	0.998
X:74521088:G:T	G177W	0.998
X:74521089:G:A	G177E	0.998
X:74524453:T:G	F224V	0.998
X:74524501:A:C	S240R	0.998
X:74524503:C:A	S240R	0.998
X:74524503:C:G	S240R	0.998
X:74529303:G:C	G421R	0.998
X:74529316:G:A	G425D	0.998
X:74529381:G:C	A447P	0.998
X:74529387:G:C	G449R	0.998
X:74529388:G:A	G449D	0.998

dbSNP variants (sampled 300 via entrez): RS1000038875 (X:74487027 A>G), RS1000045066 (X:74430474 T>C), RS1000069583 (X:74481552 C>G), RS1000121553 (X:74482032 G>C), RS1000121799 (X:74517574 G>A), RS1000150394 (X:74485723 G>A), RS1000169093 (X:74482299 G>T), RS1000175186 (X:74516943 C>A), RS1000228359 (X:74470362 C>A), RS1000266519 (X:74436531 G>A), RS1000283648 (X:74454865 A>G), RS1000325630 (X:74460947 G>A), RS1000336493 (X:74529775 C>T), RS1000399500 (X:74461369 T>C), RS1000533285 (X:74466131 G>A)

Disease associations

OMIM: gene MIM:300095 | disease phenotypes: MIM:300523, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
Allan-Herndon-Dudley syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Allan-Herndon-Dudley syndrome	Definitive	XL

Mondo (4): Allan-Herndon-Dudley syndrome (MONDO:0010354), intellectual disability (MONDO:0001071), hereditary spastic paraplegia (MONDO:0019064), prostate cancer (MONDO:0008315)

Orphanet (4): Allan-Herndon-Dudley syndrome (Orphanet:59), Hereditary spastic paraplegia (Orphanet:685), Familial prostate cancer (Orphanet:1331), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

79 total (30 of 79 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000252	Microcephaly
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000341	Narrow forehead
HP:0000395	Prominent antihelix
HP:0000400	Macrotia
HP:0000549	Abnormal conjugate eye movement
HP:0000639	Nystagmus
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000767	Pectus excavatum
HP:0000821	Hypothyroidism
HP:0000822	Hypertension
HP:0000975	Hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001266	Choreoathetosis
HP:0001319	Neonatal hypotonia
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001371	Flexion contracture
HP:0001419	X-linked recessive inheritance
HP:0001518	Small for gestational age
HP:0001531	Failure to thrive in infancy

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C537047	Allan-Herndon-Dudley syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724590 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC16 family of monocarboxylate transporters

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
6.96	IC50	110	nM	SILICRISTIN A

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	6
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	4
Benzo(a)pyrene	decreases expression, increases expression, affects methylation	3
Air Pollutants	decreases expression, increases abundance	2
Arsenic	affects cotreatment, increases abundance, increases expression, decreases expression	2
Carbamazepine	affects expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tretinoin	decreases expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	decreases expression, affects expression	2
Particulate Matter	increases abundance, decreases expression	2
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases reaction, increases uptake	1
decabromobiphenyl ether	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
fipronil	affects cotreatment, decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bosutinib	decreases reaction, increases uptake	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
jinfukang	affects cotreatment, decreases expression	1
Imatinib Mesylate	decreases reaction, increases uptake	1
Dasatinib	decreases reaction, increases uptake	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5723546	Functional	Affinity On-target Cellular interaction: (Inhibition of radiolabelled [125I]T3 uptake by target expressed in MDCK1 cells) EUB0002712a SLC16A2	Affinity On-target Cellular Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

12 cell lines: 8 induced pluripotent stem cell, 4 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4EJ	1321N1-SLC16A2-KO-c3	Cancer cell line	Male
CVCL_D4EK	1321N1-SLC16A2-KO-c6	Cancer cell line	Male
CVCL_D6KX	BIHi001-B-1	Induced pluripotent stem cell	Male
CVCL_D6KY	BIHi001-B-7	Induced pluripotent stem cell	Male
CVCL_D6KZ	BIHi001-B-8	Induced pluripotent stem cell	Male
CVCL_TL67	HAP1 SLC16A2 (-) 1	Cancer cell line	Male
CVCL_XS88	HAP1 SLC16A2 (-) 2	Cancer cell line	Male
CVCL_YP61	CS58iMCT8	Induced pluripotent stem cell	Male
CVCL_YP62	CS01iMCT8	Induced pluripotent stem cell	Male
CVCL_YP63	CS01iMCT8cor	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

288 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
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT05579327	PHASE3	COMPLETED	Withdrawal of Tiratricol Treatment in Males With Monocarboxylate Transporter 8 Deficiency (MCT8 Deficiency)
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
NCT02060474	PHASE2	COMPLETED	Thyroid Hormone Analog Therapy in MCT8 Deficiency: Triac Trial Patients
NCT02396459	PHASE2	ACTIVE_NOT_RECRUITING	Triac Trial II in MCT8 Deficiency Patients
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study