ERICKA BARBOSA TRARBACH
Projetos de Pesquisa
Unidades Organizacionais
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
10 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.
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 ClaudiaCongenital 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- FGFR1 and PROKR2 rare variants found in patients with combined pituitary hormone deficiencies(2015) CORREA, Fernanda A.; TRARBACH, Ericka B.; TUSSET, Cintia; LATRONICO, Ana Claudia; MONTENEGRO, Luciana R.; CARVALHO, Luciani R.; FRANCA, Marcela M.; OTTO, Aline P.; COSTALONGA, Everlayny F.; BRITO, Vinicius N.; ABREU, Ana Paula; NISHI, Mirian Y.; JORGE, Alexander A. L.; ARNHOLD, Ivo J. P.; SIDIS, Yisrael; PITTELOUD, Nelly; MENDONCA, Berenice B.The genetic aetiology of congenital hypopituitarism (CH) is not entirely elucidated. FGFR1 and PROKR2 loss-of-function mutations are classically involved in hypogonadotrophic hypogonadism (HH), however, due to the clinical and genetic overlap of HH and CH; these genes may also be involved in the pathogenesis of CH. Using a candidate gene approach, we screened 156 Brazilian patients with combined pituitary hormone deficiencies (CPHD) for loss-of-function mutations in FGFR1 and PROKR2. We identified three FGFR1 variants (p.Arg448Trp, p.Ser107Leu and p.Pro772Ser) in four unrelated patients (two males) and two PROKR2 variants (p. Arg85Cys and p. Arg248Glu) in two unrelated female patients. Five of the six patients harbouring the variants had a first-degree relative that was an unaffected carrier of it. Results of functional studies indicated that the new FGFR1 variant p.Arg448Trp is a loss-of-function variant, while p.Ser107Leu and p.Pro772Ser present signalling activity similar to the wild-type form. Regarding PROKR2 variants, results from previous functional studies indicated that p.Arg85Cys moderately compromises receptor signalling through both MAPK and Ca2+ pathways while p.Arg248Glu decreases calcium mobilization but has normal MAPK activity. The presence of loss-of-function variants of FGFR1 and PROKR2 in our patients with CPHD is indicative of an adjuvant and/or modifier effect of these rare variants on the phenotype. The presence of the same variants in unaffected relatives implies that they cannot solely cause the phenotype. Other associated genetic and/or environmental modifiers may play a role in the aetiology of this condition.
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- New genetic findings in a large cohort of congenital hypogonadotropic hypogonadism(2019) AMATO, Lorena Guimaraes Lima; MONTENEGRO, Luciana Ribeiro; LERARIO, Antonio Marcondes; JORGE, Alexander Augusto Lima; GUERRA JUNIOR, Gil; SCHNOLL, Caroline; RENCK, Alessandra Covallero; TRARBACH, Ericka Barbosa; COSTA, Elaine Maria Frade; MENDONCA, Berenice Bilharinho; LATRONICO, Ana Claudia; SILVEIRA, Leticia Ferreira GontijoContext: Congenital hypogonadotropic hypogonadism (CHH) is a rare condition caused by GnRH deficiency. Several genes have been associated with the pathogenesis of CHH, but most cases still remain without a molecular diagnosis. The advent of next-generation sequencing (NGS) has allowed the simultaneous genotyping of several regions, faster, making possible the extension of the genetic knowledge of CHH. Objective: Genetic characterization of a large cohort of Brazilian CHH patients. Design and patients: A cohort of 130 unrelated patients (91 males, 39 females) with CHH (75 normosmic CHH, 55 Kallmann syndrome) was studied using a panel containing 36 CHH-associated genes. Results: Potential pathogenic or probably pathogenic variants were identified in 43 (33%) CHH patients. The genes ANOS1, FGFR1 and GNRHR were the most frequently affected. A novel homozygous splice site mutation was identified in the GNRH1 gene and a deletion of the entire coding sequence was identified in SOX10. Deleterious variants in the IGSF10 gene were identified in two patients with reversible normosmic CHH. Notably, 6.9% of the patients had rare variants in more than one gene. Rare variants were also identified in SPRY4, IL17RD, FGF17, IGSF1 and FLRT3 genes. Conclusions: This is a large study of the molecular genetics of CHH providing new genetic findings for this complex and heterogeneous genetic condition. NGS has been shown to be a fast, reliable and effective tool in the molecular diagnosis of congenital CHH and being able to targeting clinical genetic testing in the future.
- Combined use of multiplex ligation-dependent probe amplification and automatic sequencing for identification of KAL1 defects in patients with Kallmann syndrome(2013) MONTENEGRO, Luciana Ribeiro; SILVEIRA, Leticia F. G.; TUSSET, Cintia; CASTRO, Margaret de; VERSIANI, Beatriz R.; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; TRARBACH, Ericka B.Objective: To investigate the role of KAL1 abnormalities in Brazilian patients with Kallmann syndrome. Design: In vitro experiments. Setting: Academic medical center. Patient(s): One hundred fifteen Brazilian patients (98 men) with Kallmann syndrome. Intervention(s): Peripheral blood leukocytes were used to obtain DNA. Main Outcome Measure(s): Direct sequencing and multiplex ligation-dependent probe amplification were used to identify KAL1 abnormalities. Result(s): We identified four KAL1 mutations (p.Met1?, p.Ala33Glyfs, p.Arg257*, and p.Trp462*) and two multiple exon deletions (exons 1-2 and 3-14) in six new male patients. Overall, 17 KAL1 defects (14.8%) were identified in the entire cohort of patients with Kallmann syndrome, including previously studied cases. KAL1-mutated patients presented with a more severe reproductive and nonreproductive phenotype (synkinesia, renal malformations, cryptorchidism, and anatomic olfactory abnormalities) in comparison with patients without KAL1 mutations. Intragenic deletions were one of the most often encountered defects (29.4%). These deletions can be missed by polymerase chain reaction (PCR) due to Yq11.2 KAL1 pseudogene (KALP) spurious amplification. Conclusion(s): These results indicate that intragenic multiexon deletions are one of the most frequent KAL1 abnormalities, which can be more accurately detected by multiplex ligation-dependent probe amplification. In addition, KAL1 sequencing results should be interpreted with caution, and stringency conditions of the PCR reaction should be adjusted to avoid pseudogene amplification. (C) 2013 by American Society for Reproductive Medicine.
- Role of gonadotropin-releasing hormone receptor mutations in patients with a wide spectrum of pubertal delay(2014) BENEDUZZI, Daiane; TRARBACH, Ericka B.; MIN, Le; JORGE, Alexander A. L.; GARMES, Heraldo M.; RENK, Alessandra Covallero; FICHNA, Marta; FICHNA, Piotr; ARANTES, Karina A.; COSTA, Elaine M. F.; ZHANG, Anna; ADEOLA, Oluwaseun; WEN, Junping; CARROLL, Rona S.; MENDONCA, Berenice B.; KAISER, Ursula B.; LATRONICO, Ana Claudia; SILVEIRA, Leticia F. G.Objective: To analyze the GNRHR in patients with normosmic isolated hypogonadotropic hypogonadism (IHH) and constitutional delay of growth and puberty (CDGP). Design: Molecular analysis and in vitro experiments correlated with phenotype. Setting: Academic medical center. Patient(s): A total of 110 individuals with normosmic IHH (74 male patients) and 50 with CDGP. Intervention(s): GNRHR coding region was amplified and sequenced. Main Outcome Measure(s): Novel variants were submitted to in vitro analysis. Frequency of mutations and genotype-phenotype correlation were analyzed. Microsatellite markers flanking GNRHR were examined in patients carrying the same mutation to investigate a possible founder effect. Result(s): Eleven IHH patients (10%) carried biallelic GNRHR mutations. In vitro analysis of novel variants (p.Y283H and p.V134G) demonstrated complete inactivation. The founder effect study revealed that Brazilian patients carrying the p.R139H mutation shared the same haplotype. Phenotypic spectrum in patients with GNRHR mutations varied from complete GnRH deficiency to partial and reversible IHH, with a relatively good genotype-phenotype correlation. One boy with CDGP was heterozygous for the p.Q106R variant, which was not considered to be pathogenic. Conclusion(s): GNRHR mutations are a frequent cause of congenital normosmic IHH and should be the first candidate gene for genetic screening in this condition, especially in autosomal recessive familial cases. The founder effect study suggested that the p.R139H mutation arises from a common ancestor in the Brazilian population. Finally, mutations in GNRHR do not appear to be involved in the pathogenesis of CDGP. (C) 2014 by American Society for Reproductive Medicine.
- New Insights Into Pheochromocytoma Surveillance of Young Patients With VHL Missense Mutations(2019) FAGUNDES, Gustavo F. C.; PETENUCI, Janaina; JR, Delmar M. Lourenco; TRARBACH, Ericka B.; PEREIRA, Maria Adelaide A.; D'EUR, Joya Emilie Correa; HOFF, Ana O.; LERARIO, Antonio M.; ZERBINI, Maria Claudia N.; SIQUEIRA, Sheila; YAMAUCHI, Fernando; SROUGI, Victor; TANNO, Fabio Y.; CHAMBO, Jose Luis; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; V, Maria Candida B. Fragoso; ALMEIDA, Madson Q.Context: Von Hippel-Lindau (VHL) disease is an autosomal dominant syndrome caused by germline mutations in the VHL gene. Guidelines recommend pheochromocytoma (PHEO) biochemical screening should start at age 5 years. Objective: Genotype-phenotype correlations in VHL, focusing on PHEO penetrance in children, were studied. Design: We retrospectively evaluated 31 individuals (median age at diagnosis was 26 years) with diagnosed VHL disease. Results: PHEO was diagnosed in six children with VHL. A large PHEO (5 cm) was detected in a 4-yearold boy with p.Gly114Ser mutation. PHEO penetrance was 55% starting at age 4 years. VHL missense mutations were identified in 11 of 22 families (50%), frameshift mutations in four (18.2%), stop codon in three (13.6%), splicing site in two (9.1%), and large gene deletion in two (9.1%). The codon 167 (n = 10) was a hotspot for VHL mutations and was significantly associated with PHEO (90% vs. 38%; P = 0.007). PHEOs and pancreatic neuroendocrine tumors (PNETs) were strongly associated with VHL missense mutations compared with other mutations (89.5% vs. 0% and 73.7% vs. 16.7%; P = 0.0001 and 0.002, respectively). In contrast, pancreatic cysts (91.7% vs. 26.3%; P = 0.0001), renal cysts (66.7% vs. 26.3%; P = 0.027), and central nervous system hemangioblastomas (91.7% vs. 47.3%; P = 0.012) were more frequent in VHL with nonmissense mutations. Conclusion: VHL missense mutations were highly associated with PHEO and PNETs. Our data support that in children with VHL harboring missense mutations, biochemical screening for PHEO should be initiated at diagnosis.
- 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 ClaudiaContext: 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.
- Novel mutation in the gonadotropin-releasing hormone receptor (GNRHR) gene in a patient with normosmic isolated hypogonadotropic hypogonadism(2012) BENEDUZZI, Daiane; TRARBACH, Ericka B.; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho de; SILVEIRA, Leticia F. G.We report a novel GNRHR mutation in a male with normosmic isolated hypogonadotropic hypogonadism (nIHH). The coding region of the GNRHR gene was amplified and sequenced. Three variants p.[Asn10Lys; Gln11Lys]; [Tyr283His] were identified in the GNRHR coding region in a male with sporadic complete nIHH. The three variants were absent in the controls (130 normal adults). Familial segregation showed that the previously described p. Asn10Lys and p. Gln11Lys are in the same allele, in compound heterozygozity with the novel variant p. Tyr283His. The p.[Asn10Lys; Gln11Lys] are known inactivating mutations. The p. Tyr283His affects a well-conserved residue, and in silico analysis suggested it is a deleterious variant. We describe a novel GNRHR mutation in a male with nIHH. Absence of the mutation in the control group, conservation among species, in silico analysis, and familial segregation suggest that p. Tyr283His, which was identified in compound heterozygozity with the p.[Asn10Lys; Gln11Lys] variants, is an inactivating mutation.