LETICIA FERREIRA GONTIJO SILVEIRA

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LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina

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  • article 8 Citação(ões) na Scopus
    Clinical and molecular aspects of congenital isolated hypogonadotropic hypogonadism
    (2011) TUSSET, Cintia; TRARBACH, Ericka B.; SILVEIRA, Leticia Ferreira Gontijo; BENEDUZZI, Daiane; MONTENEGRO, Luciana; LATRONICO, Ana Claudia
    Congenital isolated hypogonadotropic hypogonadism (IHH) is characterized by partial or complete lack of pubertal development due to defects in migration, synthesis, secretion or action of gonadotropin-releasing hormone (GnRH). Laboratory diagnosis is based on the presence of low levels of sex steroids, associated with low or inappropriately normal levels of pituitary gonadotropins (LH and FSH). Secretion of other pituitary hormones is normal, as well magnetic resonance imaging of the hypothalamohypophyseal tract, which shows absence of an anatomical defects. When IHH is associated with olfactory abnormalities (anosmia or hyposmia), it characterizes Kallmann syndrome. A growing list of genes is involved in the etiology of IHH, suggesting the heterogeneity and complexity of the genetic bases of this condition. Defects in olfactory and GnRH neuron migration are the etiopathogenic basis of Kallmann syndrome. Mutations in KAL1, FGFR1/FGF8, PROK2/PROKR2, NELF, CHD7, HS6ST1 and WDR11 are associated with defects in neuronal migration, leading to Kallmann syndrome. Notably, defects in FGFR1, FGF8, PROKR2, CHD7 and WDR11 are also associated with IHH, without olfactory abnormalities (normosmic IHH), although in a lower frequency. Mutations in KISS1R, TAC3/TACR3 and GNRH1/GNRHR are described exclusively in patients with normosmic IHH. In this paper, we reviewed the clinical, hormonal and genetic aspects of IHH. Arq Bras Endocrinol Metab. 2011;55(8):501-11
  • article 0 Citação(ões) na Scopus
    Nonsense Mutations in FGF8 Gene Causing Different Degrees of Human Gonadotropin-Releasing Deficiency (vol 95, pg 3491, 2010)
    (2011) TRARBACH, Ericka B.; ABREU, Ana Paula; FERREIRA, Leticia; SILVEIRA, Gontijo; GARMES, Heraldo Mendes; BAPTISTA, Maria TerezaM.; TELES, Milena Gurgel; COSTA, ElaineM. F.; MOHAMMADI, Moosa; PITTELOUD, Nelly; MENDONCA, Berenice B.; LATRONICO, Ana Claudia
  • article 39 Citação(ões) na Scopus
    New genetic factors implicated in human GnRH-dependent precocious puberty: The role of kisspeptin system
    (2011) TELES, Milena Gurgel; SILVEIRA, Leticia Ferreira Gontijo; TUSSET, Cintia; LATRONICO, Ana Claudia
    Human puberty is triggered by the reemergence of GnRH pulsatile secretion with progressive activation of the gonadal function. A number of genes have been identified in the complex regulatory neuroendocrine network that controls puberty initiation. KISS1 and KISS1R genes, which encode kisspeptin and its cognate receptor, respectively, are considered crucial factors for acquisition of normal reproductive function. Recently, rare missense mutations and single nucleotide polymorphisms (SNPs) of the kisspeptin system were associated with puberty onset. Two gain-of-function mutations of the KISS1 and KISS1R genes were implicated in the pathogenesis of GnRH-dependent precocious puberty, previously considered idiopathic. These discoveries have yielded significant insights into the physiology and pathophysiology of this important life transition time. Here, we review the current molecular defects that are implicated in human GnRH-dependent precocious puberty.
  • article 9 Citação(ões) na Scopus
    Mutational analysis of the necdin gene in patients with congenital isolated hypogonadotropic hypogonadism
    (2011) BENEDUZZI, Daiane; IYER, Anita K.; TRARBACH, Ericka Barbosa; SILVEIRA-NETO, Acacio P.; SILVEIRA, Leticia G.; TUSSET, Cintia; YIP, Kathleen; MENDONCA, Berenice B.; MELLON, Pamela L.; LATRONICO, Ana Claudia
    Context: Necdin activates GNRH gene expression and is fundamental for the development, migration, and axonal extension of murine GNRH neurons. In humans, necdin plays a potential role in the hypogonadotropic hypogonadism phenotype in patients with Prader-Willi syndrome. Aim: To investigate necdin gene (NDN) variants in patients with isolated hypogonadotropic hypogonadism (IHH). Patients and methods: We studied 160 Brazilian patients with IHH, which includes 92 with Kallmann syndrome and 68 with normosmic IHH. Genomic DNA was extracted and the single NDN exon was amplified and sequenced. To measure GNRH transcriptional activity, luciferase reporter plasmids containing GNRH regulatory regions were transiently transfected into GT1-7 cells in the presence and absence of overexpressed wild-type or mutant necdin. Results: A heterozygous variant of necdin, p.V318A, was identified in a 23-year-old male with Kallmann syndrome. The p.V318A was also present in affected aunt and his father and was absent in 100 Brazilian control subjects. Previous FGFR1 gene analysis revealed a missense mutation (p.P366L) in this family. Functional studies revealed a minor difference in the activation of GNRH transcription by mutant protein compared with wild type in that a significant impairment of the necdin protein activity threshold was observed. Conclusion: A rare variant of necdin (p.V318A) was described in a family with Kallmann syndrome associated with a FGFR1 mutation. Familial segregation and in vitro analysis suggested that this non-synonymous variant did not have a direct causative role in the hypogonadism phenotype. NDN mutations are not a frequent cause of congenital IHH.