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
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article 6 Citação(ões) na Scopus Mutations in insulin-like growth factor receptor 1 gene (IGF1R) resulting in intrauterine and postnatal growth retardation(2011) LEAL, Andrea de Castro; CANTON, Ana Pinheiro Machado; MONTENEGRO, Luciana Ribeiro; COUTINHO, Debora Cabral; ARNHOLD, Ivo Jorge Prado; JORGE, Alexander Augusto de LimaApproximately 10% of children born small-for-gestational age (SGA) do not show spontaneous growth catch-up. The causes of this deficit in prenatal growth and its maintenance after birth are not completely known, in most cases. Over the past eight years, several heterozygous inactivating mutations and deletions in IGF1R gene have been reported, indicating the role of defects in the IGFs/IGF1R axis as a cause of growth deficit. It has been hypothesized that at least 2.5% of children born SGA may have IGF1R gene defects. The clinical presentation of these patients is highly variable in the severity of growth retardation and hormonal parameters. In the most evident cases, patients have microcephaly, mild cognitive impairment and high levels of IGF-1, associated with short stature of prenatal onset. This review will describe the clinical, molecular and treatment of short stature with hrGH of children with mutations in the IGF1R gene. Arq Bras Endocrinol Metab. 2011;55(8):541-9- Genotype-Phenotype Correlations in Central Precocious Puberty Caused by MKRN3 Mutations (vol 106, pg 1041, 2021)(2021) SERAPHIM, C. E.; CANTON, A. P. M.; MONTENEGRO, L.; PIOVESAN, M. R.; MACEDO, D. B.; CUNHA, M.; GUIMARAES, A.; RAMOS, C. O.; BENEDETTI, A. F. F.; LEAL, De Castro A.; GAGLIARDI, P. C.; ANTONINI, S. R.; GRYNGARTEN, M.; ARCARI, A. J.; ABREU, A. P.; KAISER, U. B.; SORIANO-GUILLEN, L.; ESCRIBANO-MUNOZ, A.; CORRIPIO, R.; I, J. Labarta; TRAVIESO-SUAREZ, L.; V, N. Ortiz-Cabrera; ARGENTE, J.; MENDONCA, B. B.; BRITO, V. N.; LATRONICO, A. C.
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.
- Wide spectrum of NR5A1-related phenotypes in 46,XY and 46,XX individuals(2016) DOMENICE, Sorahia; MACHADO, Aline Zamboni; FERREIRA, Frederico Moraes; FERRAZ-DE-SOUZA, Bruno; LERARIO, Antonio Marcondes; LIN, Lin; NISHI, Mirian Yumie; GOMES, Nathalia Lisboa; SILVA, Thatiana Evelin da; SILVA, Rosana Barbosa; CORREA, Rafaela Vieira; MONTENEGRO, Luciana Ribeiro; NARCISO, Amanda; COSTA, Elaine Maria Frade; ACHERMANN, John C.; MENDONCA, Berenice BilharinhoSteroidogenic factor 1 (NR5A1, SF-1, Ad4BP) is a transcriptional regulator of genes involved in adrenal and gonadal development and function. Mutations in NR5A1 have been among the most frequently identified genetic causes of gonadal development disorders and are associated with a wide phenotypic spectrum. In 46,XY individuals, NR5A1-related phenotypes may range from disorders of sex development (DSD) to oligo/azoospermia, and in 46,XX individuals, from 46,XX ovotesticular and testicular DSD to primary ovarian insufficiency (POI). The most common 46,XY phenotype is atypical or female external genitalia with clitoromegaly, palpable gonads, and absence of Mullerian derivatives. Notably, an undervirilized external genitalia is frequently seen at birth, while spontaneous virilization may occur later, at puberty. In 46,XX individuals, NR5A1 mutations are a rare genetic cause of POI, manifesting as primary or secondary amenorrhea, infertility, hypoestrogenism, and elevated gonadotropin levels. Mothers and sisters of 46,XY DSD patients carrying heterozygous NR5A1 mutations may develop POI, and therefore require appropriate counseling. Moreover, the recurrent heterozygous p.Arg92Trp NR5A1 mutation is associated with variable degrees of testis development in 46,XX patients. A clear genotype-phenotype correlation is not seen in patients bearing NR5A1 mutations, suggesting that genetic modifiers, such as pathogenic variants in other testis/ovarian-determining genes, may contribute to the phenotypic expression. Here, we review the published literature on NR5A1-related disease, and discuss our findings at a single tertiary center in Brazil, including ten novel NR5A1 mutations identified in 46,XY DSD patients. The ever-expanding phenotypic range associated with NR5A1 variants in XY and XX individuals confirms its pivotal role in reproductive biology, and should alert clinicians to the possibility of NR5A1 defects in a variety of phenotypes presenting with gonadal dysfunction. Birth Defects Research (Part C) 108:309-320, 2016. (c) 2016 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.
- High-throughput Sequencing to Identify Monogenic Etiologies in a Preselected Polycystic Ovary Syndrome Cohort(2022) CRESPO, Raiane P.; ROCHA, Thais P.; MONTENEGRO, Luciana R.; NISHI, Mirian Y.; JORGE, Alexander A. L.; MACIEL, Gustavo A. R.; BARACAT, Edmund; LATRONICO, Ana Claudia; MENDONCA, Berenice B.; GOMES, Larissa G.Context: Polycystic ovary syndrome (PCOS) etiology remains to be elucidated, but familial clustering and twin studies have shown a strong heritable component. Objective: The purpose of this study was to identify rare genetic variants that are associated with the etiology of PCOS in a preselected cohort. Methods: This prospective study was conducted among a selected group of women with PCOS. The study's inclusion criteria were patients with PCOS diagnosed by the Rotterdam criteria with the following phenotypes: severe insulin resistance (IR), normoandrogenic-normometabolic phenotype, adrenal hyperandrogenism, primary amenorrhea, and familial PCOS. Forty-five patients were studied by target sequencing, while 8 familial cases were studied by whole exome sequencing. Results: Patients were grouped according to the inclusion criteria with the following distribution: 22 (41.5%) with severe IR, 13 (24.5%) with adrenal hyperandrogenism, 7 (13.2%) with normoandrogenic phenotype, 3 (5.7%) with primary amenorrhea, and 8 (15.1%) familial cases. DNA sequencing analysis identified 1 pathogenic variant in LMNA, 3 likely pathogenic variants in INSR, PIK3R1, and DLK1, and 6 variants of uncertain significance level with interesting biologic rationale in 5 genes (LMNA, GATA4, NR5A1, BMP15, and FSHR). LMNA was the most prevalent affected gene in this cohort (3 variants). Conclusion: Several rare variants in genes related to IR were identified in women with PCOS. Although IR is a common feature of PCOS, patients with extreme or atypical phenotype should be carefully evaluated to rule out monogenic conditions.
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
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 Claudia- Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum(2021) NAKAGUMA, Marilena; FERREIRA, Nathalia Garcia Bianchi Pereira; BENEDETTI, Anna Flavia Figueredo; MADI, Mariana Cotarelli; SILVA, Juliana Moreira; LI, Jun Z.; MA, Qianyi; OZEL, Ayse Bilge; FANG, Qing; NARCIZO, Amanda de Moraes; CARDOSO, Lais Cavalca; MONTENEGRO, Luciana Ribeiro; FUNARI, Mariana Ferreira de Assis; NISHI, Mirian Yumie; ARNHOLD, Ivo Jorge Prado; JORGE, Alexander Augusto de Lima; MENDONCA, Berenice Bilharinho de; CAMPER, Sally Ann; CARVALHO, Luciani R.We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (Delta Delta G = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations.