Molecular and gene network analysis of thyroid transcription factor 1 (TTF1) and enhanced at puberty (EAP1) genes in patients with GnRH-dependent pubertal disorders

Priscilla Cukier, Hollis Wright, Tomke Rulfs, Leticia Ferreira Gontijo Silveira, Milena Gurgel Teles, Berenice Bilharinho Mendonca, Ivo J.P. Arnhold, Sabine Heger, Ana Claudia Latronico, Sergio R. Ojeda, Vinicius Nahime Brito

    Research output: Contribution to journalArticle

    15 Scopus citations

    Abstract

    Background/Aim: TTF1 and EAP1 are transcription factors that modulate gonadotropin-releasing hormone expression. We investigated the contribution of TTF1 and EAP1 genes to central pubertal disorders. Patients and Methods: 133 patients with central pubertal disorders were studied: 86 with central precocious puberty and 47 with normosmic isolated hypogonadotropic hypogonadism. The coding region of TTF1 and EAP1 were sequenced. Variations of polyglutamine and polyalanine repeats in EAP1 were analyzed by GeneScan software. Association of TTF1 and EAP1 to genes implicated in timing of puberty was investigated by meta-network framework GeneMANIA and Cytoscape software. Results: Direct sequencing of the TTF1 did not reveal any mutation or polymorphisms. Four EAP1 synonymous variants were identified with similar frequencies among groups. The most common EAP1 5′-distal polyalanine genotype was the homozygous 12/12, but the genotype 12/9 was identified in 2 central precocious puberty sisters without functional alteration in EAP1 transcriptional activity. TTF1 and EAP1 were connected, via genetic networks, to genes implicated in the control of menarche. Conclusion: No TTF1 or EAP1 germline mutations were associated with central pubertal disorders. TTF1 and EAP1 may affect puberty by changing expression in response to other members of puberty-associated gene networks, or by differentially affecting the expression of gene components of these networks.

    Original languageEnglish (US)
    Pages (from-to)257-266
    Number of pages10
    JournalHormone Research in Paediatrics
    Volume80
    Issue number4
    DOIs
    StatePublished - Oct 1 2013

    Keywords

    • Central precocious puberty
    • EAP1
    • Hypogonadotropic hypogonadism
    • Hypothalamic hamartoma
    • TTF1

    ASJC Scopus subject areas

    • Pediatrics, Perinatology, and Child Health
    • Endocrinology, Diabetes and Metabolism
    • Endocrinology

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    Cukier, P., Wright, H., Rulfs, T., Silveira, L. F. G., Teles, M. G., Mendonca, B. B., Arnhold, I. J. P., Heger, S., Latronico, A. C., Ojeda, S. R., & Brito, V. N. (2013). Molecular and gene network analysis of thyroid transcription factor 1 (TTF1) and enhanced at puberty (EAP1) genes in patients with GnRH-dependent pubertal disorders. Hormone Research in Paediatrics, 80(4), 257-266. https://doi.org/10.1159/000354643