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Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations

Visser, W Edward; Jansen, Jurgen; Frieserna, Edith C; Kester, Monique H. A.; Mancilla, Edna; Lundgren, Johan LU ; van der Knaap, Marjo S.; Lunsing, Roelineke J.; Brouwar, Oebele F. and Visser, Theo J. (2009) In Human Mutation 30(1). p.29-38
Abstract
Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably... (More)
Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3 responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501 del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
monocarboxylate transporter 8, SLC16A2, mental retardation, novel, genotype-phenotype relation, thyroid hormone transport, MCT8
in
Human Mutation
volume
30
issue
1
pages
29 - 38
publisher
John Wiley & Sons
external identifiers
  • wos:000263096300005
  • scopus:58349086340
ISSN
1059-7794
DOI
10.1002/humu.20808
language
English
LU publication?
yes
id
e0a3163f-34d8-43f4-96af-56270e61bdc0 (old id 1293838)
date added to LUP
2012-01-18 13:50:02
date last changed
2017-11-19 03:34:48
@article{e0a3163f-34d8-43f4-96af-56270e61bdc0,
  abstract     = {Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 arc associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501 del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3 responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501 del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.},
  author       = {Visser, W Edward and Jansen, Jurgen and Frieserna, Edith C and Kester, Monique H. A. and Mancilla, Edna and Lundgren, Johan and van der Knaap, Marjo S. and Lunsing, Roelineke J. and Brouwar, Oebele F. and Visser, Theo J.},
  issn         = {1059-7794},
  keyword      = {monocarboxylate transporter 8,SLC16A2,mental retardation,novel,genotype-phenotype relation,thyroid hormone transport,MCT8},
  language     = {eng},
  number       = {1},
  pages        = {29--38},
  publisher    = {John Wiley & Sons},
  series       = {Human Mutation},
  title        = {Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations},
  url          = {http://dx.doi.org/10.1002/humu.20808},
  volume       = {30},
  year         = {2009},
}