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Metabolic Brain Disease

, Volume 34, Issue 6, pp 1565–1575 | Cite as

Novel mutations in SLC16A2 associated with a less severe phenotype of MCT8 deficiency

  • Silvia Masnada
  • Stefan Groenweg
  • Veronica Saletti
  • Luisa Chiapparini
  • Barbara Castellotti
  • Ettore Salsano
  • W. Edward Visser
  • Davide TondutiEmail author
Original Article
  • 159 Downloads

Abstract

Mutations in the thyroid hormone transporter MCT8 cause severe intellectual and motor disability and abnormal serum thyroid function tests, a syndrome known as MCT8 deficiency (or: Allan-Herndon-Dudley syndrome, AHDS). Although the majority of patients are unable to sit or walk independently and do not develop any speech, some are able to walk and talk in simple sentences. Here, we report on two cases with such a less severe clinical phenotype and consequent gross delay in diagnosis. Genetic analyses revealed two novel hemizygous mutations in the SLC16A2 gene resulting in a p.Thr239Pro and a p.Leu543Pro substitution in the MCT8 protein. In vitro studies in transiently transfected COS-1 and JEG-3 cells, and ex vivo studies in patient-derived fibroblasts revealed substantial residual uptake capacity of both mutant proteins (Leu543Pro > Thr239Pro), providing an explanation for the less severe clinical phenotype. Both mutations impair MCT8 protein stability and interfere with proper subcellular trafficking. In one of the patients calcifications were observed in the basal ganglia at the age of 29 years; an abnormal neuroradiological feature at this age that has been linked to untreated (congenital) hypothyroidism and neural cretinism. Our studies extend on previous work by identifying two novel pathogenic mutations in SLC16A2 gene resulting in a mild clinical phenotype.

Keywords

MCT8 Leukoencephalopathy Cerebral calcifications MCT8 deficiency Thyroid hormone Thyroid hormone transporter 

Notes

Acknowledgements

We thank Ramona E.A. van Heerebeek and Selmar Leeuwenburgh for the technical assistance, the Optical Imaging Center (Erasmus Medical Center Rotterdam) for technical support regarding the confocal imaging studies, and the physicians of the involved patients and healthy controls for providing the fibroblasts.

Financial support

This work was supported by a grant from the Netherlands Organisation for Health Research and Development (project number 113303005) (to WEV), from the Sherman Foundation (to WEV).

Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.

Disclosure statement

The authors have nothing to disclose.

References

  1. Arii J, Tanabe Y, Makino M, Sato H, Kohno Y (2002) Children with irreversible brain damage associated with hypothyroidism and multiple intracranial calcifications. J Child Neurol 17(4):309–313.  https://doi.org/10.1177/088307380201700416 CrossRefPubMedGoogle Scholar
  2. Capri Y, Friesema EC, Kersseboom S, Touraine R, Monnier A, Eymard-Pierre E, Des Portes V, De Michele G, Brady AF, Boespflug-Tanguy O, Visser TJ, Vaurs-Barriere C (2013) Relevance of different cellular models in determining the effects of mutations on SLC16A2/MCT8 thyroid hormone transporter function and genotype-phenotype correlation. Hum Mutat 34(7):1018–1025.  https://doi.org/10.1002/humu.22331 CrossRefPubMedGoogle Scholar
  3. de Menezes-Filho HC, Marui S, Manna TD, Brust ES, Radonsky V, Kuperman H, Dichtchekenian V, Setian N, Damiani D (2011) Novel mutation in MCT8 gene in a Brazilian boy with thyroid hormone resistance and severe neurologic abnormalities. Arq Bras Endocrinol Metabol 55(1):60–66.  https://doi.org/10.1590/S0004-27302011000100008 CrossRefGoogle Scholar
  4. Dumitrescu AM, Liao XH, Best TB, Brockmann K, Refetoff S (2004) A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 74(1):168–175.  https://doi.org/10.1086/380999 CrossRefPubMedGoogle Scholar
  5. Friesema EC, Ganguly S, Abdalla A, Manning Fox JE, Halestrap AP, Visser TJ (2003) Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter. J Biol Chem 278(41):40128–40135.  https://doi.org/10.1074/jbc.M300909200 CrossRefPubMedGoogle Scholar
  6. 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):1435–1437.  https://doi.org/10.1016/S0140-6736(04)17226-7 CrossRefPubMedGoogle Scholar
  7. Friesema EC, Kuiper GG, Jansen J, Visser TJ, Kester MH (2006) Thyroid hormone transport by the human monocarboxylate transporter 8 and its rate-limiting role in intracellular metabolism. Mol Endocrinol 20(11):2761–2772.  https://doi.org/10.1210/me.2005-0256 CrossRefPubMedGoogle Scholar
  8. Friesema EC, Jansen J, Jachtenberg JW, Visser WE, Kester MH, Visser TJ (2008) Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10. Mol Endocrinol 22(6):1357–1369.  https://doi.org/10.1210/me.2007-0112 CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gereben B, Zavacki AM, Ribich S, Kim BW, Huang SA, Simonides WS, Zeold A, Bianco AC (2008) Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 29(7):898–938.  https://doi.org/10.1210/er.2008-0019 CrossRefPubMedPubMedCentralGoogle Scholar
  10. Groeneweg S, Friesema EC, Kersseboom S, Klootwijk W, Visser WE, Peeters RP, Visser TJ (2014) The role of Arg445 and Asp498 in the human thyroid hormone transporter MCT8. Endocrinology 155(2):618–626.  https://doi.org/10.1210/en.2013-1521 CrossRefPubMedGoogle Scholar
  11. Groeneweg S, Peeters RP, Visser TJ, Visser WE (2016) Diagnostic and therapeutic challenges in the Allan–Herndon–Dudley syndrome. US Endocrinology 12(2):90–93.  https://doi.org/10.17925/USE.2016.12.02.90 CrossRefGoogle Scholar
  12. Groeneweg S, Lima de Souza EC, Meima ME, Peeters RP, Visser WE, Visser TJ (2017a) Outward-Open Model of Thyroid Hormone Transporter Monocarboxylate Transporter 8 Provides Novel Structural and Functional Insights. Endocrinology 158(10):3292–3306.  https://doi.org/10.1210/en.2017-00082 CrossRefPubMedGoogle Scholar
  13. Groeneweg S, Visser WE, Visser TJ (2017b) Disorder of thyroid hormone transport into the tissues. Best Pract Res Clin Endocrinol Metab 31(2):241–253.  https://doi.org/10.1016/j.beem.2017.05.001 CrossRefPubMedGoogle Scholar
  14. Groeneweg S, van den Berge A, Meima ME, Peeters RP, Visser TJ, Visser WE (2018) Effects of chemical chaperones on thyroid hormone transport by MCT8 mutants in patient-derived fibroblasts. Endocrinology 159(3):1290–1302.  https://doi.org/10.1210/en.2017-00846 CrossRefPubMedGoogle Scholar
  15. Halpern JP, Boyages SC, Maberly GF, Collins JK, Eastman CJ, Morris JG (1991) The neurology of endemic cretinism. A study of two endemias. Brain 114(Pt 2):825–841CrossRefGoogle Scholar
  16. Hennemann G, Docter R, Friesema EC, de Jong M, Krenning EP, Visser TJ (2001) Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability. Endocr Rev 22(4):451–476.  https://doi.org/10.1210/edrv.22.4.0435 CrossRefPubMedGoogle Scholar
  17. Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Gruters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ (2007) Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. J Clin Endocrinol Metab 92(6):2378–2381.  https://doi.org/10.1210/jc.2006-2570 CrossRefPubMedGoogle Scholar
  18. Johannes J, Jayarama-Naidu R, Meyer F, Wirth EK, Schweizer U, Schomburg L, Kohrle J, Renko K (2016) Silychristin, a Flavonolignan derived from the Milk thistle, is a potent inhibitor of the thyroid hormone transporter MCT8. Endocrinology 157(4):1694–1701.  https://doi.org/10.1210/en.2015-1933 CrossRefPubMedGoogle Scholar
  19. Kim JH, Kim YM, Yum MS, Choi JH, Lee BH, Kim GH, Yoo HW (2015) Clinical and endocrine features of two Allan-Herndon-Dudley syndrome patients with monocarboxylate transporter 8 mutations. Horm Res Paediatr 83(4):288–292.  https://doi.org/10.1159/000371466 CrossRefPubMedGoogle Scholar
  20. La Piana R, Vanasse M, Brais B, Bernard G (2015) Myelination delay and Allan-Herndon-Dudley syndrome caused by a novel mutation in the SLC16A2 gene. J Child Neurol 30(10):1371–1374.  https://doi.org/10.1177/0883073814555189 CrossRefPubMedGoogle Scholar
  21. Matheus MG, Lehman RK, Bonilha L, Holden KR (2015) Redefining the pediatric phenotype of X-linked Monocarboxylate transporter 8 (MCT8) deficiency: implications for diagnosis and therapies. J Child Neurol.  https://doi.org/10.1177/0883073815578524 CrossRefGoogle Scholar
  22. Mayerl S, Muller J, Bauer R, Richert S, Kassmann CM, Darras VM, Buder K, Boelen A, Visser TJ, Heuer H (2014) Transporters MCT8 and OATP1C1 maintain murine brain thyroid hormone homeostasis. J Clin Invest 124(5):1987–1999.  https://doi.org/10.1172/JCI70324 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Mol JA, Visser TJ (1985) Synthesis and some properties of sulfate esters and sulfamates of iodothyronines. Endocrinology 117(1):1–7.  https://doi.org/10.1210/endo-117-1-1 CrossRefPubMedGoogle Scholar
  24. Novara F, Groeneweg S, Freri E, Estienne M, Reho P, Matricardi S, Castellotti B, Visser WE, Zuffardi O, Visser TJ (2017) Clinical and molecular characteristics of SLC16A2 (MCT8) mutations in three families with the Allan-Herndon-Dudley syndrome. Hum Mutat 38(3):260–264.  https://doi.org/10.1002/humu.23140 CrossRefPubMedGoogle Scholar
  25. Ono E, Ariga M, Oshima S, Hayakawa M, Imai M, Ochiai Y, Mochizuki H, Namba N, Ozono K, Miyata I (2016) Three novel mutations of the MCT8 (SLC16A2) gene: individual and temporal variations of endocrinological and radiological features. Clin Pediatr Endocrinol 25(2):23–35.  https://doi.org/10.1297/cpe.25.23 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 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 (2005) Allan-Herndon-Dudley syndrome and the monocarboxylate transporter 8 (MCT8) gene. Am J Hum Genet 77(1):41–53.  https://doi.org/10.1086/431313 CrossRefPubMedPubMedCentralGoogle Scholar
  27. Stevenson RE, Goodman HO, Schwartz CE, Simensen RJ, McLean WT Jr, Herndon CN (1990) Allan-Herndon syndrome. I. Clinical studies. Am J Hum Genet 47(3):446–453PubMedPubMedCentralGoogle Scholar
  28. Tonduti D, Vanderver A, Berardinelli A, Schmidt JL, Collins CD, Novara F, Genni AD, Mita A, Triulzi F, Brunstrom-Hernandez JE, Zuffardi O, Balottin U, Orcesi S (2013) MCT8 deficiency: extrapyramidal symptoms and delayed myelination as prominent features. J Child Neurol 28(6):795–800.  https://doi.org/10.1177/0883073812450944 CrossRefPubMedGoogle Scholar
  29. Vatine GD, Al-Ahmad A, Barriga BK, Svendsen S, Salim A, Garcia L, Garcia VJ, Ho R, Yucer N, Qian T, Lim RG, Wu J, Thompson LM, Spivia WR, Chen Z, Van Eyk J, Palecek SP, Refetoff S, Shusta EV, Svendsen CN (2017) Modeling psychomotor retardation using iPSCs from MCT8-deficient patients indicates a prominent role for the blood-brain barrier. Cell Stem Cell 20(6):831–843 e5.  https://doi.org/10.1016/j.stem.2017.04.002 CrossRefPubMedPubMedCentralGoogle Scholar
  30. Vaurs-Barriere C, Deville M, Sarret C, Giraud G, Des Portes V, Prats-Vinas JM, De Michele G, Dan B, Brady AF, Boespflug-Tanguy O, Touraine R (2009) Pelizaeus-Merzbacher-like disease presentation of MCT8 mutated male subjects. Ann Neurol 65(1):114–118.  https://doi.org/10.1002/ana.21579 CrossRefPubMedGoogle Scholar
  31. Visser WE, Jansen J, Friesema EC, Kester MH, Mancilla E, Lundgren J, van der Knaap MS, Lunsing RJ, Brouwer OF, Visser TJ (2009) Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations. Hum Mutat 30(1):29–38.  https://doi.org/10.1002/humu.20808 CrossRefPubMedGoogle Scholar
  32. Yen PM (2001) Physiological and molecular basis of thyroid hormone action. Physiol Rev 81(3):1097–1142.  https://doi.org/10.1152/physrev.2001.81.3.1097 CrossRefPubMedGoogle Scholar
  33. Yen PM, Ando S, Feng X, Liu Y, Maruvada P, Xia X (2006) Thyroid hormone action at the cellular, genomic and target gene levels. Mol Cell Endocrinol 246(1-2):121–127.  https://doi.org/10.1016/j.mce.2005.11.030 CrossRefPubMedGoogle Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Pediatric Neurology UnitV. Buzzi Children’s HospitalMilanItaly
  2. 2.Department of Brain and Behavioural SciencesUniversity of PaviaPaviaItaly
  3. 3.Department of Internal Medicine, Academic Center for Thyroid DiseasesErasmus MC, University Medical CenterRotterdamThe Netherlands
  4. 4.Child Neurology DepartmentIRCCS Foundation C. Besta Neurological InstituteMilanItaly
  5. 5.Neuroradiology UnitIRCCS Foundation C. Besta Neurological InstituteMilanItaly
  6. 6.Unit of Genetics of Neurodegenerative and Metabolic DiseasesIRCCS Foundation C. Besta Neurological InstituteMilanItaly
  7. 7.Unit of Neurodegenerative and Neurometabolic Rare DiseasesIRCCS Foundation C. Besta Neurological InstituteMilanItaly

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