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Cited by 24Thyroid Disorders and TreatmentsGenomics and Rare DiseasesMetabolism and Genetic Disorders

Transcriptional profiling of fibroblasts from patients with mutations in MCT8 and comparative analysis with the human brain transcriptome

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Visser, W. Edward, Swagemakers, Sigrid M.A., Őzgűr, Zeliha, Schot, Rachel, Verheijen, Frans W., van Ijcken, Wilfred F.J., van der Spek, Peter J., Visser, Theo J.·2010·Human Molecular Genetics
DOI 10.1093/hmg/ddq337PMC PMC2951866
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Abstract

Thyroid hormone (TH) is crucial for normal brain development. TH transporters control TH homeostasis in brain as evidenced by the complex endocrine and neurological phenotype of patients with mutations in monocarboxylate transporter 8 (MCT8). We investigated the mechanisms of disease by analyzing gene expression profiles in fibroblasts from patients with MCT8 mutations. Studying MCT8 and its transcriptional context in different comprehensive spatial and temporal human brain transcriptome data sets revealed distinct region-specific MCT8 expression. Furthermore, MCT8 demonstrated a clear age-dependent decrease, suggesting its importance in early brain development. Performing comparative transcriptome analysis, we linked the genes differentially expressed (DE) in patient fibroblasts to the human brain transcriptome. DE genes in patient fibroblasts were strongly over-represented among genes highly correlated with MCT8 expression in brain. Furthermore, using the same approach we identified which genes in the classical TH signaling pathway are affected in patients. Finally, we provide evidence that the TRα2 receptor variant is closely connected to MCT8. The present study provides a molecular basis for understanding which pathways are likely affected in the brains of patients with mutations in MCT8. Our data regarding a functional relationship between MCT8 and TRα2 suggest an unanticipated role for TRα2 in the (patho)physiology of TH signaling in the brain. This study demonstrates how genome-wide expression data from patient-derived non-neuronal tissue related to the human brain transcriptome may be successfully employed to improve our understanding of neurological disease.

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  • MCT8-deficient patient fibroblasts and human cell lines do not harbor the characteristics of affected neural or endothelial cells required for a relevant human cell-based disease model of AHDS.

    “While these cell models showed some features of MCT8 deficiency, they do not harbor the characteristics of affected neural or endothelial cells that are required for a relevant human cell-based disease model of AHDS.”

    From Modeling Psychomotor Retardation using iPSCs from MCT8-Deficient Patients Indicates a Prominent Role for the Blood-Brain Barrier (2017) · cites this paper as Visser et al., 2010

    The Discussion (page not provided) cautions that abnormalities found in patients’ peripheral cells may not reflect abnormalities in the brain, supporting a limitation of fibroblast models. But the paper does not establish that the fibroblasts or human cell lines lack the required characteristics of affected neural or endothelial cells; it instead describes its fibroblast–brain transcriptome comparison as informative for understanding the disease. (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Visser, W. E., Swagemakers, S. M. A., Őzgűr, Z., Schot, R., Verheijen, F. W., van Ijcken, W. F. J., van der Spek, P. J., & Visser, T. J.
Affiliations
  • Erasmus MC (NL)
  • Cancer Genomics Centre (NL)
Corresponding author
Visser, W. Edward
ORCID
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2010-08-12
Volume
19
Issue
21
Pages
4189-4200
ISSN
  • 0964-6906 (ISSN-L)
  • 1460-2083
DOI
10.1093/hmg/ddq337
PMC
PMC2951866
OpenAlex
W2104249959
Cited by
24
References
5
Citations by year
2025: 2 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 1 · 2018: 3 · 2017: 3 · 2016: 2 · 2014: 1 · 2013: 3 · 2012: 2
FWCI
1.69
Type
journal article
Language
en
Open access
Licence
cc-by-nc
Locations
  • Human Molecular Genetics (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
  • EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
  • RePub (Erasmus University Rotterdam) (submittedVersion)
Funders
Nederlandse Organisatie voor Wetenschappelijk Onderzoek
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
Keywords
MCT8, thyroid hormone transport, thyroid hormone signaling, fibroblast gene expression, human brain transcriptome, brain development, age-related gene expression, differentially expressed genes, neurological disorders, genotype-phenotype correlation
MeSH terms
Brain, Humans, Mutation, Transcription, Genetic, Gene Expression Profiling, Monocarboxylic Acid Transporters, Symporters

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