TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy

J. Martijn Bos, Malayannan Subramaniam, John R Hawse, Imke Christiaans, Nalini M. Rajamannan, Joseph Maleszewski, William D. Edwards, Arthur A M Wilde, Thomas C. Spelsberg, Michael John Ackerman

Research output: Contribution to journalArticle

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Abstract

Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFβ Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2 â± 23 years, MLVWT 20.8 â± 4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM.

Original languageEnglish (US)
Pages (from-to)1896-1903
Number of pages8
JournalJournal of Cellular Biochemistry
Volume113
Issue number6
DOIs
StatePublished - Jun 2012

Fingerprint

Hypertrophic Cardiomyopathy
Genes
Mutation
Heart Diseases
Up-Regulation
Immunohistochemistry
Assays
Gene Knockout Techniques
Pituitary Neoplasms
Missense Mutation
Mutagenesis
Site-Directed Mutagenesis
Luciferases
DNA Sequence Analysis
Oncogenes
Knockout Mice
Transfection
Exons
Proteins
Cardiovascular Diseases

Keywords

  • GENETICS
  • HYPERTROPHIC CARDIOMYOPATHY
  • TGFβ
  • TIEG1

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy. / Bos, J. Martijn; Subramaniam, Malayannan; Hawse, John R; Christiaans, Imke; Rajamannan, Nalini M.; Maleszewski, Joseph; Edwards, William D.; Wilde, Arthur A M; Spelsberg, Thomas C.; Ackerman, Michael John.

In: Journal of Cellular Biochemistry, Vol. 113, No. 6, 06.2012, p. 1896-1903.

Research output: Contribution to journalArticle

Bos, JM, Subramaniam, M, Hawse, JR, Christiaans, I, Rajamannan, NM, Maleszewski, J, Edwards, WD, Wilde, AAM, Spelsberg, TC & Ackerman, MJ 2012, 'TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy', Journal of Cellular Biochemistry, vol. 113, no. 6, pp. 1896-1903. https://doi.org/10.1002/jcb.24058
Bos, J. Martijn ; Subramaniam, Malayannan ; Hawse, John R ; Christiaans, Imke ; Rajamannan, Nalini M. ; Maleszewski, Joseph ; Edwards, William D. ; Wilde, Arthur A M ; Spelsberg, Thomas C. ; Ackerman, Michael John. / TGFβ-inducible early gene-1 (TIEG1) mutations in hypertrophic cardiomyopathy. In: Journal of Cellular Biochemistry. 2012 ; Vol. 113, No. 6. pp. 1896-1903.
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abstract = "Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiovascular disease. A recent study showed that male KLF10-encoded TGFβ Inducible Early Gene-1 knock-out mice (TIEG-/-) develop HCM with 13-fold up-regulation of PTTG1-encoded pituitary tumor-transforming gene 1. We hypothesized TIEG1 could be a novel candidate gene in the pathogenesis of genotype negative HCM in humans, possibly through a loss of its repression on PTTG1 expression. A cohort of 923 unrelated patients from two independent HCM centers was analyzed for mutations in TIEG's four translated exons using DHPLC and direct DNA-sequencing. Site directed mutagenesis was performed to clone novel variants. The effect of TIEG1 mutations on SMAD7 and PTTG1 promoters was studied using transient transfection and luciferase-assays. Altered expression of PTTG1 in cardiac tissue was studied by immunohistochemistry (IHC) to determine levels of PTTG1 protein in hypertrophic diseases. Six novel TIEG1 missense mutations were discovered in six patients (two males/four females, mean age at diagnosis 56.2 {\^a}± 23 years, MLVWT 20.8 {\^a}± 4 mm). Compared to WT TIEG1, five TIEG1 mutants significantly increased PTTG1 promoter function similar to TIEG1-/--mice. By IHC, PTTG1-protein expression was significantly increased in multiple models of hypertrophic cardiac disease, including TIEG1-mutation positive HCM compared to normal hearts. This is the first article to associate mutations in TIEG1 to human disease with the discovery of six novel, HCM-associated variants. Functional assays suggest a role for PTTG1 in the pathogenesis of TIEG1-mediated HCM. Up-regulation of PTTG1 seems to be a common pathway in hypertrophic heart disease, including TIEG1-mediated HCM.",
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