Monocarboxylate transporter 8

Solute carrier family 16, member 2 (thyroid hormone transporter)
Identifiers
Symbols	SLC16A2 ; AHDS; DXS128; DXS128E; MCT 7; MCT 8; MCT7; MCT8; MRX22; XPCT
External IDs	OMIM: 300095 MGI: 1203732 HomoloGene: 39495 IUPHAR: 992 GeneCards: SLC16A2 Gene
Gene ontology Molecular function • transporter activity • monocarboxylic acid transmembrane transporter activity • symporter activity • thyroid hormone transmembrane transporter activity Cellular component • integral component of plasma membrane • membrane Biological process • transport • monocarboxylic acid transport • ion transmembrane transport • thyroid hormone transport Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	6567	20502
Ensembl	ENSG00000147100	ENSMUSG00000033965
UniProt	P36021	O70324
RefSeq (mRNA)	NM_006517	NM_009197
RefSeq (protein)	NP_006508	NP_033223
Location (UCSC)	Chr X: 74.42 – 74.53 Mb	Chr X: 103.7 – 103.82 Mb
PubMed search

Monocarboxylate transporter 8 (MCT8) is an active transporter protein that in humans is encoded by the SLC16A2 gene.^[1][2][3][4]

Function

MCT8 actively transports a variety of iodo-thyronines including the thyroid hormones T₃ and T₄.^[2]

Clinical significance

A genetic disorder (discovered in 2003^[2] and 2004^[5]) is caused by mutation in the transporter of thyroid hormone, MCT8, also known as SLC16A2, is believed to be account for a significant fraction of the undiagnosed neurological disorders (usually resulting in hypotonic/floppy infants with delayed milestones). This genetic defect was known as Allan-Herndon-Dudley syndrome (since 1944) without knowing its actual cause. It has been shown mutated in cases of X-linked leukoencephalopathy.^[6] Some of the symptoms for this disorder as are follows: normal to slightly elevated TSH, elevated T₃ and reduced T₄ (ratio of T₃/T₄ is about double its normal value). Normal looking at birth and for the first few years, hypotonic (floppy), in particular difficulty to hold the head, possibly difficulty to thrive, possibly with delayed myelination (if so, some cases are reported with an MRI pattern similar to Pelizaeus-Merzbacher disease, known as PMD^[7]), possibly with decreased mitochondrial enzyme activities, possibly with fluctuating lactate level. Patients have an alert face, a limited IQ, patients may never talk/walk, 50% need feeding tube, patients have a normal life span. This disease can be ruled out with a simple TSH/T₄/T₃ thyroid test.

Model organisms

Slc16a2 knockout mouse phenotype

Characteristic	Phenotype
Homozygote viability	Normal
Fertility	Normal
Body weight	Normal
Anxiety	Normal
Neurological assessment	Normal
Grip strength	Normal
Hot plate	Normal
Dysmorphology	Normal
Indirect calorimetry	Normal
Glucose tolerance test	Abnormal[8]
Auditory brainstem response	Normal
DEXA	Normal
Radiography	Normal
Body temperature	Normal
Eye morphology	Normal
Clinical chemistry	Abnormal[9]
Haematology	Normal
Micronucleus test	Normal
Heart weight	Normal
Salmonella infection	Abnormal[10]
Citrobacter infection	Normal[11]
All tests and analysis from[12][13]

Mice

A conditional knockout mouse line, called Slc16a2^{tm1a(KOMP)Wtsi[14][15]} was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.^[16][17][18]

Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.^[12][19] Twenty one tests were carried out on mutant mice and three significant abnormalities were observed.^[12] Female homozygote mutants had decreased circulating glucose levels. Male hemizygous mutants had an increased susceptibility to bacterial infection. Both sexes had various abnormal plasma chemistry parameters.^[12]

Zebrafish

A knockout zebrafish line was generated in 2014 using the zinc-finger nuclease (ZFN)-mediated targeted gene editing system.^[20] Similar to human patients, the zebrafish larvae exhibited neurological and behavioral deficiencies. They demonstrated reduced locomotor activity, altered myelin-related genes and neuron-specific deficiencies in circuit formation.^[21]

See also

• Solute carrier family

References

1. Lafrenière RG, Carrel L, Willard HF (Jul 1994). "A novel transmembrane transporter encoded by the XPCT gene in Xq13.2". Human Molecular Genetics 3 (7): 1133–9. doi:10.1093/hmg/3.7.1133. PMID 7981683.
2. Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ (Oct 2003). "Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter". The Journal of Biological Chemistry 278 (41): 40128–35. doi:10.1074/jbc.M300909200. PMID 12871948.
3. Schwartz CE, May MM, Carpenter NJ, Rogers RC, Martin J, Bialer MG, Ward J, Sanabria J, Marsa S, Lewis JA, Echeverri R, Lubs HA, Voeller K, Simensen RJ, Stevenson RE (Jul 2005). "Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene". American Journal of Human Genetics 77 (1): 41–53. doi:10.1086/431313. PMC 1226193. PMID 15889350.
4. "Entrez Gene: SLC16A2 solute carrier family 16, member 2 (monocarboxylic acid transporter 8)".
5. Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S (Jan 2004). "A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene". American Journal of Human Genetics 74 (1): 168–75. doi:10.1086/380999. PMC 1181904. PMID 14661163.
6. Tsurusaki Y, Osaka H, Hamanoue H, Shimbo H, Tsuji M, Doi H, Saitsu H, Matsumoto N, Miyake N (Sep 2011). "Rapid detection of a mutation causing X-linked leucoencephalopathy by exome sequencing". Journal of Medical Genetics 48 (9): 606–9. doi:10.1136/jmg.2010.083535. PMID 21415082.
7. Vaurs-Barrière C, Deville M, Sarret C, Giraud G, Des Portes V, Prats-Viñas JM, De Michele G, Dan B, Brady AF, Boespflug-Tanguy O, Touraine R (Jan 2009). "Pelizaeus-Merzbacher-Like disease presentation of MCT8 mutated male subjects". Annals of Neurology 65 (1): 114–8. doi:10.1002/ana.21579. PMID 19194886.
8. "Glucose tolerance test data for Slc16a2". Wellcome Trust Sanger Institute.
9. "Clinical chemistry data for Slc16a2". Wellcome Trust Sanger Institute.
10. "Salmonella infection data for Slc16a2". Wellcome Trust Sanger Institute.
11. "Citrobacter infection data for Slc16a2". Wellcome Trust Sanger Institute.
12. Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput characterisation of knockout mice". Acta Ophthalmologica 88: 925–7. doi:10.1111/j.1755-3768.2010.4142.x.
13. Mouse Resources Portal, Wellcome Trust Sanger Institute.
14. "International Knockout Mouse Consortium".
15. "Mouse Genome Informatics".
16. Skarnes WC, Rosen B, West AP, Koutsourakis M, Bushell W, Iyer V, Mujica AO, Thomas M, Harrow J, Cox T, Jackson D, Severin J, Biggs P, Fu J, Nefedov M, de Jong PJ, Stewart AF, Bradley A (Jun 2011). "A conditional knockout resource for the genome-wide study of mouse gene function". Nature 474 (7351): 337–42. doi:10.1038/nature10163. PMC 3572410. PMID 21677750.
17. Dolgin E (Jun 2011). "Mouse library set to be knockout". Nature 474 (7351): 262–3. doi:10.1038/474262a. PMID 21677718.
18. Collins FS, Rossant J, Wurst W (Jan 2007). "A mouse for all reasons". Cell 128 (1): 9–13. doi:10.1016/j.cell.2006.12.018. PMID 17218247.
19. van der Weyden L, White JK, Adams DJ, Logan DW (2011). "The mouse genetics toolkit: revealing function and mechanism". Genome Biology 12 (6): 224. doi:10.1186/gb-2011-12-6-224. PMC 3218837. PMID 21722353.
20. Zada D, Tovin A, Lerer-Goldshtein T, Vatine GD, Appelbaum L (Sep 2014). "Altered behavioral performance and live imaging of circuit-specific neural deficiencies in a zebrafish model for psychomotor retardation". PLoS Genetics 10 (9): e1004615. doi:10.1371/journal.pgen.1004615. PMC 4177677. PMID 25255244.
21. Zada D, Tovin A, Lerer-Goldshtein T, Vatine GD, Appelbaum L (Sep 2014). "Altered behavioral performance and live imaging of circuit-specific neural deficiencies in a zebrafish model for psychomotor retardation". PLoS Genetics 10 (9): e1004615. doi:10.1371/journal.pgen.1004615. PMC 4177677. PMID 25255244.

Further reading

• Halestrap AP, Meredith D (Feb 2004). "The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond". Pflügers Archiv 447 (5): 619–28. doi:10.1007/s00424-003-1067-2. PMID 12739169.
• Friesema EC, Jansen J, Heuer H, Trajkovic M, Bauer K, Visser TJ (Sep 2006). "Mechanisms of disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8". Nature Clinical Practice. Endocrinology & Metabolism 2 (9): 512–23. doi:10.1038/ncpendmet0262. PMID 16957765.
• Grüters A (2007). "Thyroid hormone transporter defects". Endocrine Development 10: 118–26. doi:10.1159/0000106823. PMID 17684393.
• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA (Apr 1996). "A "double adaptor" method for improved shotgun library construction". Analytical Biochemistry 236 (1): 107–13. doi:10.1006/abio.1996.0138. PMID 8619474.
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA (Apr 1997). "Large-scale concatenation cDNA sequencing". Genome Research 7 (4): 353–8. doi:10.1101/gr.7.4.353. PMC 139146. PMID 9110174.
• Price NT, Jackson VN, Halestrap AP (Jan 1998). "Cloning and sequencing of four new mammalian monocarboxylate transporter (MCT) homologues confirms the existence of a transporter family with an ancient past". The Biochemical Journal. 329 ( Pt 2) (2): 321–8. PMC 1219047. PMID 9425115.
• Debrand E, Heard E, Avner P (Mar 1998). "Cloning and localization of the murine Xpct gene: evidence for complex rearrangements during the evolution of the region around the Xist gene". Genomics 48 (3): 296–303. doi:10.1006/geno.1997.5173. PMID 9545634.
• Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S (Jan 2004). "A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene". American Journal of Human Genetics 74 (1): 168–75. doi:10.1086/380999. PMC 1181904. PMID 14661163.
• Friesema EC, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MH, Kuiper GG, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ (2004). "Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation". Lancet 364 (9443): 1435–7. doi:10.1016/S0140-6736(04)17226-7. PMID 15488219.
• Heuer H, Maier MK, Iden S, Mittag J, Friesema EC, Visser TJ, Bauer K (Apr 2005). "The monocarboxylate transporter 8 linked to human psychomotor retardation is highly expressed in thyroid hormone-sensitive neuron populations". Endocrinology 146 (4): 1701–6. doi:10.1210/en.2004-1179. PMID 15661862.
• Brockmann K, Dumitrescu AM, Best TT, Hanefeld F, Refetoff S (Jun 2005). "X-linked paroxysmal dyskinesia and severe global retardation caused by defective MCT8 gene". Journal of Neurology 252 (6): 663–6. doi:10.1007/s00415-005-0713-3. PMID 15834651.
• Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH (Nov 2006). "Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism". Molecular Endocrinology 20 (11): 2761–72. doi:10.1210/me.2005-0256. PMID 16887882.
• Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (Nov 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
• Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Grüters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ (Jun 2007). "Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine". The Journal of Clinical Endocrinology and Metabolism 92 (6): 2378–81. doi:10.1210/jc.2006-2570. PMID 17356046.