LUCIANA RIBEIRO MONTENEGRO
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Clínica Médica, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
16 resultados
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conferenceObject X-Linked Central Precocious Puberty Associated with MECP2 defects(2022) CANTON, Ana; TINANO, Flavia; GUASTI, Leonardo; MONTENEGRO, Luciana; RYAN, Fiona; SHEARS, Deborah; MELO, Maria Edna; GOMES, Larissa; PIANA, Mariana; BRAUNER, Raja; ESPINO, Rafael; ESCRIBANO-MUNOZ, Arancha; PAGANONI, Alyssa; KORBONITS, Marta; SERAPHIM, Carlos Eduardo; FARIA, Aline; COSTA, Silvia; KREPISCHI, Ana Cristina; JORGE, Alexander; DAVID, Alessia; ARGENTE, Jesus; MENDONCA, Berenice; BRITO, Vinicius; HOWARD, Sasha; LATRONICO, Ana Claudia- Pathogenic variants inTNRC6Bcause a genetic disorder characterised by developmental delay/intellectual disability and a spectrum of neurobehavioural phenotypes including autism and ADHD(2020) GRANADILLO, Jorge Luis; STEGMANN, Alexander P.A.; GUO, Hui; XIA, Kun; ANGLE, Brad; BONTEMPO, Kelly; RANELLS, Judith D.; NEWKIRK, Patricia; COSTIN, Carrie; VIRONT, Joleen; STUMPEL, Constanze T.; SINNEMA, Margje; PANIS, Bianca; PFUNDT, Rolph; KRAPELS, Ingrid P. C.; KLAASSENS, Merel; NICOLAI, Joost; LI, Jinliang; JIANG, Yuwu; MARCO, Elysa; CANTON, Ana; LATRONICO, Ana Claudia; MONTENEGRO, Luciana; LEHEUP, Bruno; BONNET, Celine; AMUDHAVALLI, Shivarajan M.; LAWSON, Caitlin E.; MCWALTER, Kirsty; TELEGRAFI, Aida; PEARSON, Richard; KVARNUNG, Malin; WANG, Xia; BI, Weimin; ROSENFELD, Jill Anne; SHINAWI, MarwanBackground Rare variants in hundreds of genes have been implicated in developmental delay (DD), intellectual disability (ID) and neurobehavioural phenotypes.TNRC6Bencodes a protein important for RNA silencing. Heterozygous truncating variants have been reported in three patients from large cohorts with autism, but no full phenotypic characterisation was described. Methods Clinical and molecular characterisation was performed on 17 patients withTNRC6Bvariants. Clinical data were obtained by retrospective chart review, parent interviews, direct patient interaction with providers and formal neuropsychological evaluation. Results Clinical findings included DD/ID (17/17) (speech delay in 94% (16/17), fine motor delay in 82% (14/17) and gross motor delay in 71% (12/17) of subjects), autism or autistic traits (13/17), attention deficit and hyperactivity disorder (ADHD) (11/17), other behavioural problems (7/17) and musculoskeletal findings (12/17). Other congenital malformations or clinical findings were occasionally documented. The majority of patients exhibited some dysmorphic features but no recognisable gestalt was identified. 17 heterozygousTNRC6Bvariants were identified in 12 male and five female unrelated subjects by exome sequencing (14), a targeted panel (2) and a chromosomal microarray (1). The variants were nonsense (7), frameshift (5), splice site (2), intragenic deletions (2) and missense (1). Conclusions Variants inTNRC6Bcause a novel genetic disorder characterised by recurrent neurocognitive and behavioural phenotypes featuring DD/ID, autism, ADHD and other behavioural abnormalities. Our data highly suggest that haploinsufficiency is the most likely pathogenic mechanism.TNRC6Bshould be added to the growing list of genes of the RNA-induced silencing complex associated with ID/DD, autism and ADHD.
conferenceObject Clinical and Genetic Features of Central Precocious Puberty Associated with Complex Phenotypes(2018) CANTON, Ana; BRITO, Vinicius; MONTENEGRO, Luciana; RAMOS, Carolina; MACEDO, Delanie; BESSA, Danielle; CUNHA, Marina; JORGE, Alexander; MENDONCA, Berenice; LATRONICO, Ana Claudiaarticle 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):501-11conferenceObject Update on the etiological diagnosis of central precocious puberty in both sexes(2023) CANTON, Ana; LATRONICO, Ana Claudia; MONTENEGRO, Luciana; PIOVESAN, Maiara; SERAPHIM, Carlos; TINANO, Flavia; FARIA, Aline; MENDONCA, Berenice; BRITO, ViniciusconferenceObject PATERNALLY INHERITED DLK1 DELETION AS A NOVEL CAUSE OF FAMILIAL CENTRAL PRECOCIOUS PUBERTY(2017) DAUBER, Andrew; CUNHA-SILVA, Marina; MACEDO, Delanie; BRITO, Vinicius; ABREU, Ana Paula; ROBERTS, Stephanie; MONTENEGRO, Luciana; ANDREW, Melissa; KRIBY, Andrew; WEIRAUCH, Matthew; LABILLOY, Guillaume; BESSA, Danielle; CARROLL, Rona; JACOBS, Dakota; CHAPPELL, Patrick; MENDONCA, Berenice B.; HAIG, David; KAISER, Ursula; LATRONICO, Ana Claudia- High Prevalence of Alterations in DNA Mismatch Repair Genes of Lynch Syndrome in Pediatric Patients with Adrenocortical Tumors Carrying a Germline Mutation on TP53(2020) BRONDANI, Vania Balderrama; MONTENEGRO, Luciana; LACOMBE, Amanda Meneses Ferreira; MAGALHAES, Breno Marchiori; NISHI, Mirian Yumie; FUNARI, Mariana Ferreira de Assis; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; SIQUEIRA, Sheila Aparecida Coelho; ZERBINI, Maria Claudia Nogueira; DENES, Francisco Tibor; LATRONICO, Ana Claudia; MENDONCA, Berenice Bilharinho; ALMEIDA, Madson Queiroz; LERARIO, Antonio Marcondes; SOARES, Ibere Cauduro; FRAGOSO, Maria Candida Barisson VillaresAdrenocortical cancer is a rare malignant neoplasm associated with a dismal prognosis. Identification of the molecular pathways involved in adrenal tumorigenesis is essential for a better understanding of the disease mechanism and improvement of its treatment. The aim of this study is to define the prevalence of alterations in DNA mismatch repair (MMR) genes in Lynch syndrome among pediatric patients with adrenocortical neoplasia from southern Brazil, where the prevalence of a specific TP53 germline mutation (p.Arg337His) is quite high. Thirty-six pediatric patients were retrospectively evaluated. Immunohistochemistry (IHC) for theMMR enzymes MLH1, MSH2, MSH6, and PMS2, as well as next-generation sequencing (NGS) were performed. For IHC, 36 pediatric tumors were tested. In all of them, the expression of all evaluated MMR proteins was well-preserved. For NGS, 35 patients with pediatric tumor were tested. Three patients (8.57%) with the TP53 p.Arg337His germline mutation presented pathogenic and likely pathogenic variants in the MMR genes (two in MLH1 and one in MSH6). The prevalence of alteredMMR genes among pediatric patients was elevated (8.57%) and higher than in colorectal and endometrial cancer cohorts. Pediatric patients with adrenocortical tumors should, thus, be strongly considered as at genetic risk for Lynch syndrome.
- Novel MKRN3 Missense Mutations Associated With Central Precocious Puberty Reveal Distinct Effects on Ubiquitination(2023) MAGNOTTO, John C.; MANCINI, Alessandra; BIRD, Keisha; MONTENEGRO, Luciana; TUTUNCULER, Filiz; PEREIRA, Sidney A.; SIMAS, Vitoria; GARCIA, Leonardo; ROBERTS, Stephanie A.; MACEDO, Delanie; MAGNUSON, Melissa; GAGLIARDI, Priscila; MAURAS, Nelly; WITCHEL, Selma F.; CARROLL, Rona S.; LATRONICO, Ana Claudia; KAISER, Ursula B.; ABREU, Ana PaulaContext Loss-of-function mutations in the maternally imprinted genes, MKRN3 and DLK1, are associated with central precocious puberty (CPP). Mutations in MKRN3 are the most common known genetic etiology of CPP. Objective This work aimed to screen patients with CPP for MKRN3 and DLK1 mutations and analyze the effects of identified mutations on protein function in vitro. Methods Participants included 84 unrelated children with CPP (79 girls, 5 boys) and, when available, their first-degree relatives. Five academic medical institutions participated. Sanger sequencing of MKRN3 and DLK1 5 ' upstream flanking and coding regions was performed on DNA extracted from peripheral blood leukocytes. Western blot analysis was performed to assess protein ubiquitination profiles. Results Eight heterozygous MKRN3 mutations were identified in 9 unrelated girls with CPP. Five are novel missense mutations, 2 were previously identified in patients with CPP, and 1 is a frameshift variant not previously associated with CPP. No pathogenic variants were identified in DLK1. Girls with MKRN3 mutations had an earlier age of initial pubertal signs and higher basal serum luteinizing hormone and follicle-stimulating hormone compared to girls with CPP without MRKN3 mutations. Western blot analysis revealed that compared to wild-type MKRN3, mutations within the RING finger domain reduced ubiquitination whereas the mutations outside this domain increased ubiquitination. Conclusion MKRN3 mutations were present in 10.7% of our CPP cohort, consistent with previous studies. The novel identified mutations in different domains of MKRN3 revealed different patterns of ubiquitination, suggesting distinct molecular mechanisms by which the loss of MRKN3 results in early pubertal onset.
conferenceObject Investigation of imprinting alterations in MKRN3 and DLK1 in a cohort of girls with central precocious puberty through specific DNA methylation analysis(2019) CANTON, Ana; STEUNOU, Virginie; BRITO, Vinicius; SOBRIER, Marie Laure; MONTENEGRO, Luciana; BESSA, Danielle; MENDONCA, Berenice B.; NETCHINE, Irene; LATRONICO, Ana Claudia- Familial central precocious puberty due to DLK1 deficiency: novel genetic findings and relevance of serum DLK1 levels(2023) MONTENEGRO, Luciana; SERAPHIM, Carlos; TINANO, Flavia; PIOVESAN, Maiara; CANTON, Ana P. M.; MCELREAVEY, Ken; BRABANT, Severine; BORIS, Natalia P.; MAGNUSON, Melissa; CARROLL, Rona S.; KAISER, Ursula B.; ARGENTE, Jesus; BARRIOS, Vicente; BRITO, Vinicius N.; BRAUNER, Raja; LATRONICO, Ana ClaudiaBackground: Several rare loss-of-function mutations of delta-like noncanonical notch ligand 1 (DLK1) have been described in non-syndromic children with familial central precocious puberty (CPP). Objective: We investigated genetic abnormalities of DLK1 gene in a French cohort of children with idiopathic CPP. Additionally, we explored the pattern of DLK1 serum levels in patients with CPP and in healthy children at puberty, as well as in wild-type female mice. Patients and Methods: Genomic DNA was obtained from 121 French index cases with CPP. Automated sequencing of the coding region of the DLK1 gene was performed in all cases. Serum DLK1 levels were measured by enzyme linked immunosorbent assay (ELISA) in 209 individuals, including 191 with normal pubertal development and in female mice during postnatal pubertal maturation. Results: We identified 2 rare pathogenic DLK1 allelic variants: A stop gain variant (c.372C>A; p.Cys124X) and a start loss variant (c.2T>G; p.Met1?, or p.0) in 2 French girls with CPP. Mean serum DLK1 levels were similar between healthy children and idiopathic CPP children. In healthy individuals, DLK1 levels correlated with pubertal stage: In girls, DLK1 decreased between Tanner stages III and V, whereas in boys, DLK1 decreased between Tanner stages II and V (P =.008 and.016, respectively). Serum levels of Dlk1 also decreased in wild-type female mice. Conclusions: Novel loss-of-function mutations in DLK1 gene were identified in 2 French girls with CPP. Additionally, we demonstrated a pattern of dynamic changes in circulating DLK1 serum levels in humans and mice during pubertal stages, reinforcing the role of this factor in pubertal timing.