PTTG-Binding Factor (PBF) Is a Novel Regulator of the Thyroid Hormone Transporter MCT8

Read, Martin; Turnell, Andrew; Sharma, Neil; Lewy, Gregory; Fong, Jim; Seed, Robert; Kwan, Perkin; Ryan, Gavin; Mehanna, Hisham; Chan, Shiao-Yng; Darras, Veerle; Boelaert, Kristien; Franklyn, Jayne A.; McCabe, Chris

doi:10.1210/en.2011-2030

Cited by 21 publications

(26 citation statements)

References 25 publications

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“…Although MCT8 function is not dependent on basigin or embigin (24), it may well depend on other interacting proteins. The first modulating protein interaction has been shown recently between the proto-oncogene pituitary tumor-transforming gene-binding factor and MCT8 in the thyroid gland (25). Our findings of the larger immobile PM fraction of the P321L mutant may suggest a more rigid binding to interacting proteins than WT MCT8.…”

Section: Discussionsupporting

confidence: 51%

Mutations in MCT8 in Patients with Allan-Herndon-Dudley-Syndrome Affecting Its Cellular Distribution

Kersseboom¹,

Kremers²,

Friesema³

et al. 2013

Molecular Endocrinology

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Monocarboxylate transporter 8 (MCT8) is a thyroid hormone (TH)-specific transporter. Mutations in the MCT8 gene are associated with Allan-Herndon-Dudley Syndrome (AHDS), consisting of severe psychomotor retardation and disturbed TH parameters. To study the functional consequences of different MCT8 mutations in detail, we combined functional analysis in different cell types with live-cell imaging of the cellular distribution of seven mutations that we identified in patients with AHDS. We used two cell models to study the mutations in vitro: 1) transiently transfected COS1 and JEG3 cells, and 2) stably transfected Flp-in 293 cells expressing a MCT8-cyan fluorescent protein construct. All seven mutants were expressed at the protein level and showed a defect in T3 and T4 transport in uptake and metabolism studies. Three mutants (G282C, P537L, and G558D) had residual uptake activity in Flp-in 293 and COS1 cells, but not in JEG3 cells. Four mutants (G221R, P321L, D453V, P537L) were expressed at the plasma membrane. The mobility in the plasma membrane of P537L was similar to WT, but the mobility of P321L was altered. The other mutants studied (insV236, G282C, G558D) were predominantly localized in the endoplasmic reticulum. In essence, loss of function by MCT8 mutations can be divided in two groups: mutations that result in partial or complete loss of transport activity (G221R, P321L, D453V, P537L) and mutations that mainly disturb protein expression and trafficking (insV236, G282C, G558D). The cell type-dependent results suggest that MCT8 mutations in AHDS patients may have tissue-specific effects on TH transport probably caused by tissue-specific expression of yet unknown MCT8-interacting proteins.

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Section: Discussionsupporting

confidence: 51%

Mutations in MCT8 in Patients with Allan-Herndon-Dudley-Syndrome Affecting Its Cellular Distribution

Kersseboom¹,

Kremers²,

Friesema³

et al. 2013

Molecular Endocrinology

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“…Furthermore, on the cellular level mutant variants of MCT8 might interact differently with other ancillary proteins for proper localization at the plasma membrane and transport function. Interaction with the regulator PTTG-binding factor (PBF) has been previously demonstrated to be associated with a reduction in expression of MCT8 at the cell surface (Smith et al 2012). Finally, our data put emphasis on the general question surrounding substrate-induced or constitutive oligomerization versus monomerization (oligomer dissociation) in members of the MFS, which has not yet been elucidated.…”

Section: Discussionmentioning

confidence: 87%

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations

Fischer¹,

Kleinau²,

Müller³

et al. 2015

Journal of Molecular Endocrinology

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The monocarboxylate transporter 8 (MCT8) is a member of the major facilitator superfamily (MFS). These membrane-spanning proteins facilitate translocation of a variety of substrates, MCT8 specifically transports iodothyronines. Mutations in MCT8 are the underlying cause of severe X-linked psychomotor retardation. At the molecular level, such mutations led to deficiencies in substrate translocation due to reduced cell-surface expression, impaired substrate binding, or decreased substrate translocation capabilities. However, the causal relationships between genotypes, molecular features of mutated MCT8, and patient characteristics have not yet been comprehensively deciphered. We investigated the relationship between pathogenic mutants of MCT8 and their capacity to form dimers (presumably oligomeric structures) as a potential regulatory parameter of the transport function of MCT8. Fourteen pathogenic variants of MCT8 were investigated in vitro with respect to their capacity to form oligomers. Particular mutations close to the substrate translocation channel (S194F, A224T, L434W, and R445C) were found to inhibit dimerization of MCT8. This finding is in contrast to those for other transporters or transmembrane proteins, in which substitutions predominantly at the outer-surface inhibit oligomerization. Moreover, specific mutations of MCT8 located in transmembrane helix 2 (del230F, V235M, and ins236V) increased the capacity of MCT8 variants to dimerize. We analyzed the localization of MCT8 dimers in a cellular context, demonstrating differences in MCT8 dimer formation and distribution. In summary, our results add a new link between the functions (substrate transport) and protein organization (dimerization) of MCT8, and might be of relevance for other members of the MFS. Finally, the findings are discussed in relationship to functional data combined with structural-mechanistical insights into MCT8.

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“…The devastating neurological symptoms of humans with inactivating mutations of the gene encoding MCT8, the TH transporter, are well known (83). None of the patients we studied had the typical biological profile of this rare disease, which is observed only in male patients, but there may be other as yet unknown molecular mechanisms facilitating TH access to the developing central nervous system (84,85). It also remains possible that currently unknown underlying diseases associated with CH and increasing the risk of neurodevelopmental disorders will be identified in the future.…”

Section: Associated Malformations Chronic Diseases and Cardiovasculmentioning

confidence: 96%

ENDOCRINOLOGY AND ADOLESCENCE: Congenital hypothyroidism: a clinical update of long-term outcome in young adults

Léger

2015

European Journal of Endocrinology

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Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. The early treatment of CH patients has successfully improved the prognosis and management of this disorder. Optimal treatment and management throughout the patient's life, beginning in the neonatal period, are required to ensure long-term health. Affected patients should be offered assessments of associated medical conditions and provided with accurate information about their condition throughout their lives, but particularly during the transition from pediatric to adult services. This review provides a summary of current knowledge about the long-term outcomes of these patients and appropriate management into early adulthood. We carried out a systematic search of the Medline database to identify relevant articles. Despite major improvements in prognosis, the impact of CH is clearly not uniform, and management should take into account a broader range of relevant indicators, including CH severity, associated comorbid conditions and the adequacy of treatment during childhood and adulthood. The early diagnosis and management of associated medical conditions, and better educational strategies to improve compliance with treatment, should improve the long-term prognosis. Further studies are required to explore changes with aging.

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PTTG-Binding Factor (PBF) Is a Novel Regulator of the Thyroid Hormone Transporter MCT8

Cited by 21 publications

References 25 publications

Mutations in MCT8 in Patients with Allan-Herndon-Dudley-Syndrome Affecting Its Cellular Distribution

Mutations in MCT8 in Patients with Allan-Herndon-Dudley-Syndrome Affecting Its Cellular Distribution

Modulation of monocarboxylate transporter 8 oligomerization by specific pathogenic mutations

ENDOCRINOLOGY AND ADOLESCENCE: Congenital hypothyroidism: a clinical update of long-term outcome in young adults

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