Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes

Elizabeth A. McAninch, Sungro Jo, Nailliw Z. Preite, Erzsébet Farkas, Petra Mohácsik, Csaba Fekete, Péter Egri, Balázs Gereben, Yan Li, Youping Deng, Mary Elizabeth Patti, Chantal Zevenbergen, Robin P. Peeters, Deborah C Mash, Antonio C. Bianco

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.

Original languageEnglish (US)
Pages (from-to)920-933
Number of pages14
JournalJournal of Clinical Endocrinology and Metabolism
Volume100
Issue number3
DOIs
StatePublished - Mar 1 2015

Fingerprint

Dermatoglyphics
Polymorphism
Thyroid Hormones
Genes
Enzymes
Gene encoding
Microarrays
Brain
HEK293 Cells
Apoptosis
Cerebral Cortex
Iodide Peroxidase
Oxidative stress
Mitochondrial Proteins
Tissue Array Analysis
Ubiquitin
Intercellular Signaling Peptides and Proteins
Ubiquitination
Central Nervous System Diseases
Repair

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. / McAninch, Elizabeth A.; Jo, Sungro; Preite, Nailliw Z.; Farkas, Erzsébet; Mohácsik, Petra; Fekete, Csaba; Egri, Péter; Gereben, Balázs; Li, Yan; Deng, Youping; Patti, Mary Elizabeth; Zevenbergen, Chantal; Peeters, Robin P.; Mash, Deborah C; Bianco, Antonio C.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 100, No. 3, 01.03.2015, p. 920-933.

Research output: Contribution to journalArticle

McAninch, EA, Jo, S, Preite, NZ, Farkas, E, Mohácsik, P, Fekete, C, Egri, P, Gereben, B, Li, Y, Deng, Y, Patti, ME, Zevenbergen, C, Peeters, RP, Mash, DC & Bianco, AC 2015, 'Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes', Journal of Clinical Endocrinology and Metabolism, vol. 100, no. 3, pp. 920-933. https://doi.org/10.1210/jc.2014-4092
McAninch, Elizabeth A. ; Jo, Sungro ; Preite, Nailliw Z. ; Farkas, Erzsébet ; Mohácsik, Petra ; Fekete, Csaba ; Egri, Péter ; Gereben, Balázs ; Li, Yan ; Deng, Youping ; Patti, Mary Elizabeth ; Zevenbergen, Chantal ; Peeters, Robin P. ; Mash, Deborah C ; Bianco, Antonio C. / Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes. In: Journal of Clinical Endocrinology and Metabolism. 2015 ; Vol. 100, No. 3. pp. 920-933.
@article{50bce546670d4a1c87eae8a1da2d4422,
title = "Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes",
abstract = "Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.",
author = "McAninch, {Elizabeth A.} and Sungro Jo and Preite, {Nailliw Z.} and Erzs{\'e}bet Farkas and Petra Moh{\'a}csik and Csaba Fekete and P{\'e}ter Egri and Bal{\'a}zs Gereben and Yan Li and Youping Deng and Patti, {Mary Elizabeth} and Chantal Zevenbergen and Peeters, {Robin P.} and Mash, {Deborah C} and Bianco, {Antonio C.}",
year = "2015",
month = "3",
day = "1",
doi = "10.1210/jc.2014-4092",
language = "English (US)",
volume = "100",
pages = "920--933",
journal = "Journal of Clinical Endocrinology and Metabolism",
issn = "0021-972X",
publisher = "The Endocrine Society",
number = "3",

}

TY - JOUR

T1 - Prevalent polymorphism in thyroid hormone-activating enzyme leaves a genetic fingerprint that underlies associated clinical syndromes

AU - McAninch, Elizabeth A.

AU - Jo, Sungro

AU - Preite, Nailliw Z.

AU - Farkas, Erzsébet

AU - Mohácsik, Petra

AU - Fekete, Csaba

AU - Egri, Péter

AU - Gereben, Balázs

AU - Li, Yan

AU - Deng, Youping

AU - Patti, Mary Elizabeth

AU - Zevenbergen, Chantal

AU - Peeters, Robin P.

AU - Mash, Deborah C

AU - Bianco, Antonio C.

PY - 2015/3/1

Y1 - 2015/3/1

N2 - Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.

AB - Context: A common polymorphism in the gene encoding the activating deiodinase (Thr92Ala-D2) is known to be associated with quality of life in millions of patients with hypothyroidism and with several organ-specific conditions. This polymorphism results in a single amino acid change within the D2 molecule where its susceptibility to ubiquitination and proteasomal degradation is regulated. Objective: To define the molecular mechanisms underlying associated conditions in carriers of the Thr92Ala-D2 polymorphism. Design, Setting, Patients: Microarray analyses of 19 postmortem human cerebral cortex samples were performed to establish a foundation for molecular studies via a cell model of HEK-293 cells stably expressing Thr92 or Ala92 D2. Results: The cerebral cortex of Thr92Ala-D2 carriers exhibits a transcriptional fingerprint that includes sets of genes involved in CNS diseases, ubiquitin, mitochondrial dysfunction (chromosomal genes encoding mitochondrial proteins), inflammation, apoptosis, DNA repair, and growth factor signaling. Similar findings were made in Ala92-D2-expressing HEK-293 cells and in both cases there was no evidence that thyroid hormone signaling was affected ie, the expression level of T3-responsive genes was unchanged, but that several other genes were differentially regulated. The combined microarray analyses (brain/cells) led to the development of an 81-gene classifier that correctly predicts the genotype of homozygous brain samples. In contrast to Thr92-D2, Ala92-D2 exhibits longer half-life and was consistently found in the Golgi. A number of Golgi-related genes were down-regulated in Ala92-D2-expressing cells, but were normalized after 24-h-treatment with the antioxidant N-acetylecysteine. Conclusions: Ala92-D2 accumulates in the Golgi, where its presence and/or ensuing oxidative stress disrupts basic cellular functions and increases pre-apoptosis. These findings are reminiscent to disease mechanisms observed in other neurodegenerative disorders such as Huntington's disease, and could contribute to the unresolved neurocognitive symptoms of affected carriers.

UR - http://www.scopus.com/inward/record.url?scp=84924941823&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84924941823&partnerID=8YFLogxK

U2 - 10.1210/jc.2014-4092

DO - 10.1210/jc.2014-4092

M3 - Article

C2 - 25569702

AN - SCOPUS:84924941823

VL - 100

SP - 920

EP - 933

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

SN - 0021-972X

IS - 3

ER -