LETICIA FERREIRA GONTIJO SILVEIRA
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
7 resultados
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- Mutational analysis of TAC3 and TACR3 genes in patients with idiopathic central pubertal disorders(2012) TUSSET, Cintia; NOEL, Sekoni D.; TRARBACH, Ericka B.; SILVEIRA, Leticia F. G.; JORGE, Alexander A. L.; BRITO, Vinicius N.; CUKIER, Priscila; SEMINARA, Stephanie B.; MENDONCA, Berenice B. de; KAISER, Ursula B.; LATRONICO, Ana ClaudiaObjective: To investigate the presence of variants in the TAC3 and TACR3 genes, which encode NKB and its receptor (NK3R), respectively, in a large cohort of patients with idiopathic central pubertal disorders. Subjects and methods: Two hundred and thirty seven patients were studied: 114 with central precocious puberty (CPP), 73 with normosmic isolated hypogonadotropic hypogonadism (IHH), and 50 with constitutional delay of growth and puberty (CDGP). The control group consisted of 150 Brazilian individuals with normal pubertal development. Genomic DNA was extracted from peripheral blood and the entire coding region of both TAC3 and TACR3 genes were amplified and automatically sequenced. Results: We identified one variant (p.A63P) in NKB and four variants, p.G18D, p.L58L (c.172C > T), p.W275* and p.A449S in NK3R, which were absent in the control group. The p.A63P variant was identified in a girl with CPP, and p.A449S in a girl with CDGP. The known p.G18D, p.L58L, and p.W275* variants were identified in three unrelated males with normosmic IHH. Conclusion: Rare variants in the TAC3 and TACR3 genes were identified in patients with central pubertal disorders. Loss-of-function variants of TACR3 were associated with the normosmic IHH phenotype.
conferenceObject Apparently Sporadic Central Precocious Puberty Is Caused By Paternally Inherited Mutations in the Imprinted MKRN3 Gene(2014) ABREU, Ana Paula; MACEDO, Delanie B.; REIS, Ana Claudia Silva; MONTENEGRO, Luciana Ribeiro; DAUBER, Andrew; BENEDUZZI, Diane; CULIER, Priscilla; SILVEIRA, Leticia Gontijo; TELES, Milena Gurgel; CARROLL, Rona S.; GUERRA, Gil; GUARAGNA FILHO, Guilherme; GUCEV, Zoran Spasico; ARNHOLD, Ivo J. P.; CASTRO, Margaret; MOREIRA, Ayrton Custodio; MARTINELLI, Carlos Eduardo; HIRSCHHORN, Joel N.; MENDONASA, Berenice Bilharinho; BRITO, Vinicius N.; ANTONINI, Sonir Roberto; KAISER, Ursula B.; LATRONICO, Ana Claudia- High Frequency of MKRN3 Mutations in Male Central Precocious Puberty Previously Classified as Idiopathic(2017) BESSA, Danielle S.; MACEDO, Delanie B.; BRITO, Vinicius N.; FRANCA, Monica M.; MONTENEGRO, Luciana R.; CUNHA-SILVA, Marina; SILVEIRA, Leticia G.; HUMMEL, Tiago; BERGADA, Ignacio; BRASLAVSKY, Debora; ABREU, Ana Paula; DAUBER, Andrew; MENDONCA, Berenice B.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaBackground/Aims: Recently, loss-of-function mutations in the MKRN3 gene have been implicated in the etiology of familial central precocious puberty (CPP) in both sexes. We aimed to analyze the frequency of MKRN3 mutations in boys with CPP and to compare the clinical and hormonal features of boys with and without MKRN3 mutations. Methods: This was a retrospective review of clinical, hormonal and genetic features of 20 male patients with idiopathic CPP evaluated at an academic medical center. The entire coding regions of MKRN3, KISS1 and KISS1R genes were sequenced. Results: We studied 20 boys from 17 families with CPP. All of them had normal brain magnetic resonance imaging. Eight boys from 5 families harbored four distinct heterozygous MKRN3 mutations predicted to be deleterious for protein function, p.Ala162Glyfs*14, p.Arg213Glyfs*73, p.Arg328Cys and p. Arg365Ser. One boy carried a previously described KISS1-activating mutation (p.Pro74Ser). The frequency of MKRN3 mutations among these boys with idiopathic CPP was significantly higher than previously reported female data (40 vs. 6.4%, respectively, p < 0.001). Boys with MKRN3 mutations had typical clinical and hormonal features of CPP. Notably, they had later pubertal onset than boys without MKRN3 abnormalities (median age 8.2 vs. 7.0 years, respectively, p = 0.033). Conclusion: We demonstrated a high frequency of MKRN3 mutations in boys with CPP, previously classified as idiopathic, suggesting the importance of genetic analysis in this group. The boys with CPP due to MKRN3 mutations had classical features of CPP, but with puberty initiation at a borderline age. (C) 2016 S. Karger AG, Basel
- Absence of Functional LIN28B Mutations in a Large Cohort of Patients with Idiopathic Central Precocious Puberty(2012) SILVEIRA-NETO, Acacio P.; LEAL, Leticia Ferro; EMERMAN, Amy B.; HENDERSON, Katherine D.; PISKOUNOVA, Elena; HENDERSON, Brian E.; GREGORY, Richard I.; SILVEIRA, Leticia F. Gontijo; HIRSCHHORN, Joel N.; NGUYEN, Thutrang T.; BENEDUZZI, Daiane; TUSSET, Cintia; REIS, Ana Claudia S.; BRITO, Vinicius N.; MENDONCA, Berenice B.; PALMERT, Mark R.; ANTONINI, Sonir R.; LATRONICO, Ana ClaudiaAim: To investigate LIN28B gene variants in children with idiopathic central precocious puberty (CPP). Patients and Methods: We studied 178 Brazilian children with CPP (171 girls, 16.8% familial cases). A large multiethnic group (1,599 subjects; Multiethnic Cohort, MEC) was used as control. DNA analysis and biochemical in vitro studies were performed. Results: A heterozygous LIN28B variant, p. H199R, was identified in a girl who developed CPP at 5.2 years. This variant was absent in 310 Brazilian control individuals, but it was found in the same allele frequency in women from the MEC cohort, independent of the age of menarche. Functional studies revealed that when ectopically expressed in cells, the mutant protein was capable of binding pre-let-7 microRNA and inhibiting let-7 expression to the same extent as wild-type Lin28B protein. Other rare LIN28B variants (p.P173P, c.198+32_33delCT, g.9575731A>C and c.-11C>T) were identified in CPP patients and controls. Therefore, no functional mutation was identified. Conclusion: In vitro studies revealed that the rare LIN28B p.H199R variant identified in a girl with CPP does not affect the Lin28B function in the regulation of let-7 expression. Although LIN28B SNPs were associated with normal pubertal timing, rare variations in this gene do not seem to be commonly involved in the molecular pathogenesis of CPP.
- Molecular and Gene Network Analysis of Thyroid Transcription Factor 1 (TTF1) and Enhanced at Puberty (EAP1) Genes in Patients with GnRH-Dependent Pubertal Disorders(2013) CUKIER, Priscilla; WRIGHT, Hollis; RULFS, Tomke; SILVEIRA, Leticia Ferreira Gontijo; TELES, Milena Gurgel; MENDONCA, Berenice Bilharinho; ARNHOLD, Ivo J. P.; HEGER, Sabine; LATRONICO, Ana Claudia; OJEDA, Sergio R.; BRITO, Vinicius NahimeBackground/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. (C) 2013 S. Karger AG, Basel
- Central Precocious Puberty That Appears to Be Sporadic Caused by Paternally Inherited Mutations in the Imprinted Gene Makorin Ring Finger 3(2014) MACEDO, Delanie B.; ABREU, Ana Paula; REIS, Ana Claudia S.; MONTENEGRO, Luciana R.; DAUBER, Andrew; BENEDUZZI, Daiane; CUKIER, Priscilla; SILVEIRA, Leticia F. G.; TELES, Milena G.; CARROLL, Rona S.; GUERRA JUNIOR, Gil; GUARAGNA FILHO, Guilherme; GUCEV, Zoran; ARNHOLD, Ivo J. P.; CASTRO, Margaret de; MOREIRA, Ayrton C.; MARTINELLI JR., Carlos Eduardo; HIRSCHHORN, Joel N.; MENDONCA, Berenice B.; BRITO, Vinicius N.; ANTONINI, Sonir R.; KAISER, Ursula B.; LATRONICO, Ana ClaudiaContext: Loss-of-function mutations in makorin ring finger 3 (MKRN3), an imprinted gene located on the long arm of chromosome 15, have been recognized recently as a cause of familial central precocious puberty (CPP) in humans. MKRN3 has a potential inhibitory effect on GnRH secretion. Objectives: The objective of the study was to investigate potential MKRN3 sequence variations as well as copy number and methylation abnormalities of the 15q11 locus in patients with apparently sporadic CPP. Setting and Participants: We studied 215 unrelated children (207 girls and eight boys) from three university medical centers with a diagnosis of CPP. All but two of these patients (213 cases) reported no family history of premature sexual development. First-degree relatives of patients with identified MKRN3 variants were included for genetic analysis. Main Outcome Measures: All 215 CPP patients were screened for MKRN3 mutations by automatic sequencing. Multiplex ligation-dependent probe amplification was performed in a partially overlapping cohort of 52 patients. Results: We identified five novel heterozygous mutations in MKRN3 in eight unrelated girls with CPP. Four were frame shift mutations predicted to encode truncated proteins and one was a missense mutation, which was suggested to be deleterious by in silico analysis. All patients with MKRN3mutations had classical features of CPP with a median age of onset at 6 years. Copy number and methylation abnormalities at the 15q11 locus were not detected in the patients tested for these abnormalities. Segregation analysis was possible in five of the eight girls with MKRN3 mutations; in all cases, the mutation was inherited on the paternal allele. Conclusions: We have identified novel inherited MKRN3 defects in children with apparently sporadic CPP, supporting a fundamental role of this peptide in the suppression of the reproductive axis.
bookPart Puberdade normal e precoce(2017) BRITO, Vinicius Nahime de; LATRONICO, Ana Cláudia; SILVEIRA, Letícia Ferreira Gontijo; MENDONçA, Berenice Bilharinho de