ELAINE MARIA FRADE COSTA
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, 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
10 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 10
- 46,XY DSD due to 17 beta-HSD3 Deficiency and 5 alpha-Reductase Type 2 Deficiency(2011) INACIO, Marlene; SIRCILI, Maria Helena P.; BRITO, Vinicius N.; DOMENICE, Sorahia; OLIVEIRA-JUNIOR, Ari Alves; ARNHOLD, Ivo J. P.; TIBOR, Francisco D.; COSTA, Elaine M. F.; MENDONCA, Berenice B.
- 46,XY Disorders of Sex Development (46,XY DSD) due to Androgen Receptor Defects: Androgen Insensitivity Syndrome(2011) ARNHOLD, Ivo J. P.; MELO, Karla; COSTA, Elaine M. F.; DANILOVIC, Debora; INACIO, Marlene; DOMENICE, Sorahia; MENDONCA, Berenice B.
- Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein(2019) CHAMBERLIN, Adam; HUETHER, Robert; MACHADO, Aline Z.; GRODEN, Michael; LIU, Hsiao-Mei; UPADHYAY, Kinnari; VIVIAN, O.; GOMES, Nathalia L.; LERARIO, Antonio M.; NISHI, Mirian Y.; COSTA, Elaine M. F.; MENDONCA, Berenice; DOMENICE, Sorahia; VELASCO, Jacqueline; LOKE, Johnny; OSTRER, HarryMissense mutations in the gene, MAP3K1, are a common cause of 46,XY gonadal dysgenesis, accounting for 15-20% of cases [Ostrer, 2014, Disorders of sex development (DSDs): an update. J. Clin. Endocrinol. Metab., 99, 1503-1509]. Functional studies demonstrated that all of these mutations cause a protein gain-of-function that alters co-factor binding and increases phosphorylation of the downstream MAP kinase pathway targets, MAPK11, MAP3K and MAPK1. This dysregulation of the MAP kinase pathway results in increased CTNNB1, increased expression of WNT4 and FOXL2 and decreased expression of SRY and SOX9. Unique and recurrent pathogenic mutations cluster in three semi-contiguous domains outside the kinase region of the protein, a newly identified N-terminal domain that shares homology with the Guanine Exchange Factor (residues Met164 to Glu231), a Plant HomeoDomain (residues Met442 to Trp495) and an ARMadillo repeat domain (residues Met566 to Glu862). Despite the presence of the mutation clusters and clinical data, there exists a dearth of mechanistic insights behind the development imbalance. In this paper, we use structural modeling and functional data of these mutations to understand alterations of the MAP3K1 protein and the effects on protein folding, binding and downstream target phosphorylation. We show that these mutations have differential effects on protein binding depending on the domains in which they occur. These mutations increase the binding of the RHOA, MAP3K4 and FRAT1 proteins and generally decrease the binding of RAC1. Thus, pathologies in MAP3K1 disrupt the balance between the pro-kinase activities of the RHOA and MAP3K4 binding partners and the inhibitory activity of RAC1.
- Elevated plasma miR-210 expression is associated with atypical genitalia in patients with 46,XY differences in sex development(2022) ELIAS, Felipe Martins; NISHI, Mirian Yumi; SIRCILI, Maria Helena Palma; BASTISTA, Rafael Loch; GOMES, Nathalia Lisboa; FERRARI, Maria Tereza Martins; COSTA, Elaine Maria Frade; DENES, Francisco Tibor; MENDONCA, Berenice Bilharinho; DOMENICE, SorahiaBackground: Differences of sex development (DSD) is a term used for conditions in which the chromosomal, gonadal or phenotypical sex is atypical. 46,XY DSD patients frequently present undervirilized external genitalia. The expression of different miRNAs in many organs of the male genital system has been reported, and these miRNAs have been associated with testicular function and its disorders, but no description has been related to DSD conditions. This study aimed to evaluate the plasma expression of miR-210 in 46,XY DSD patients who presented atypical genitalia at birth. Methods: Eighteen 46,XY DSD patients who presented atypical genitalia (undescended testis and/or hypospadias, bifid scrotum or micropenis) at birth and 36 male control individuals were selected. Plasma levels of miR-210 and reference miR-23a were measured using RT-qPCR and the data were analysed by the 2(-Delta Ct) method. Results: MiR-210 plasma levels were significantly higher in 46,XY DSD patients with atypical genitalia than in male control subjects (p = 0.0024). A positive association between miR-210 levels and the presence of cryptorchidism and hypospadias (p = 0.0146 and p = 0.0223) was found in these patients. Significantly higher levels of miR-210 were observed in patients with 46,XY DSD and cryptorchidism than in control subjects (p = 0.0118). These results are in agreement with previous literature reports, in which increased levels of miR-210 expression were observed in human testicular tissue from adult males with undescended testes in comparison with samples of descended testes. Conclusion: Our study showed a positive association between the presence of atypical genitalia and plasma levels of miR-210 expression in the group of patients with 46,XY DSD of unknown aetiology studied. These findings contribute to reveal a new perspective on the role of miRNAs in the development of male external genitalia and the broad spectrum of phenotypes presented by patients with 46,XY DSD.
- MAMLD1 (Mastermind-Like Domain Containing 1) Homozygous Gain-of-Function Missense Mutation Causing 46,XX Disorder of Sex Development in a Virilized Female(2011) BRANDAO, Maira Pontual; COSTA, Elaine Maria Frade; FUKAMI, Maki; GERDULO, Mariza; PEREIRA, Natalia P.; DOMENICE, Sorahia; OGATA, Tsutomu; MENDONCA, Berenice B.
- Identification of the first homozygous 1-bp deletion in GDF9 gene leading to primary ovarian insufficiency by using targeted massively parallel sequencing(2018) FRANCA, M. M.; FUNARI, M. F. A.; NISHI, M. Y.; NARCIZO, A. M.; DOMENICE, S.; COSTA, E. M. F.; LERARIO, A. M.; MENDONCA, B. B.Targeted massively parallel sequencing (TMPS) has been used in genetic diagnosis for Mendelian disorders. In the past few years, the TMPS has identified new and already described genes associated with primary ovarian insufficiency (POI) phenotype. Here, we performed a targeted gene sequencing to find a genetic diagnosis in idiopathic cases of Brazilian POI cohort. A custom SureSelect(XT) DNA target enrichment panel was designed and the sequencing was performed on Illumina NextSeq sequencer. We identified 1 homozygous 1-bp deletion variant (c.783delC) in the GDF9 gene in 1 patient with POI. The variant was confirmed and segregated using Sanger sequencing. The c.783delC GDF9 variant changed an amino acid creating a premature termination codon (p.Ser262Hisfs*2). This variant was not present in all public databases (ExAC/gnomAD, NHLBI/EVS and 1000Genomes). Moreover, it was absent in 400 alleles from fertile Brazilian women screened by Sanger sequencing. The patient's mother and her unaffected sister carried the c.783delC variant in a heterozygous state, as expected for an autosomal recessive inheritance. Here, the TMPS identified the first homozygous 1-bp deletion variant in GDF9. This finding reveals a novel inheritance pattern of pathogenic variant in GDF9 associated with POI, thus improving the genetic diagnosis of this disorder.
- Absence of inactivating mutations and deletions in the DMRT1 and FGF9 genes in a large cohort of 46,XY patients with gonadal dysgenesis(2012) MACHADO, Aline Zamboni; SILVA, Thatiana Evilen da; COSTA, Elaine Maria Frade; SANTOS, Mariza Gerdulo dos; NISHI, Mirian Yumie; BRITO, Vinicius Nahime; MENDONCA, Berenice Bilharinho; DOMENICE, SorahiaDespite advances in our understanding of the mechanisms involved in sex determination and differentiation, the specific roles of many genes in these processes are not completely understood in humans. Both DMRT1 and FGF9 are among this group of genes. Dmrt1 controls germ cell differentiation, proliferation, migration and pluripotency and Sertoli cell proliferation and differentiation. Fgf9 has been considered a critical factor in early testicular development and germ cell survival in mice. We screened for the presence of DMRT1 and FGF9 mutations in 33 patients with 46,XY gonadal dysgenesis. No deletions in either DMRT1 or FGF9 were identified using the MLPA technique. Eight allelic variants of DMRT1 were identified, and in silico analysis suggested that the novel c.968-15insTTCTCTCT variant and the c.774G>C (rs146975077) variant could have potentially deleterious effects on the DMRT1 protein. Nine previously described FGF9 allelic variants and six different alleles of the 3' UTR microsatellite were identified. However, none of these DMRT1 or FGF9 variants was associated with increased 46,XY gonadal dysgenesis. In conclusion, our study suggests that neither DMRT1 nor FGF9 abnormalities are frequently involved in dysgenetic male gonad development in patients with non-syndromic 46,XY disorder of sex development. (C) 2012 Published by Elsevier Masson SAS.
- Androgen receptor mRNA analysis from whole blood: a low-cost strategy for detection of androgen receptor gene splicing defects(2018) SILVA, Juliana M.; BATISTA, Rafael Loch; RODRIGUES, Andresa De Santi; NISHI, Mirian Y.; COSTA, Elaine M. F.; DOMENICE, Sorahia; CARVALHO, Luciani R. S.; MENDONCA, Berenice B.
- Assembling the jigsaw puzzle: CBX2 isoform 2 and its targets in disorders/differences of sex development(2018) SPROLL, Patrick; EID, Wassim; GOMES, Camila R.; MENDONCA, Berenice B.; GOMES, Nathalia L.; COSTA, Elaine M. -F.; BIASON-LAUBER, AnnaBackgroundOne of the defining moments of human life occurs early during embryonic development, when individuals sexually differentiate into either male or female. Perturbation of this process can lead to disorders/differences of sex development (DSD). Chromobox protein homolog 2 (CBX2) has two distinct isoforms, CBX2.1 and CBX2.2: the role of CBX2.1 in DSD has been previously established, yet to date the function of the smaller isoform CBX2.2 remains unknown. MethodsThe genomic DNA of two 46,XY DSD patients was analysed using whole exome sequencing. Furthermore, protein/DNA interaction studies were performed using DNA adenine methyltransferase identification (DamID) to identify putative binding partners of CBX2. Finally, invitro functional studies were used to elucidate the effect of wild-type and variant CBX2.2 on selected downstream targets. ResultsHere, we describe two patients with features of DSD i.e. atypical external genitalia, perineal hypospadias and no palpable gonads, each patient carrying a distinct CBX2.2 variant, p.Cys132Arg (c.394T>C) and p.Cys154fs (c.460delT). We show that both CBX2.2 variants fail to regulate the expression of genes essential for sexual development, leading to a severe 46,XY DSD defect, likely because of a defective expression of EMX2 in the developing gonad. ConclusionOur study indicates a distinct function of the shorter form of CBX2 and by identifying several of its unique targets, can advance our understanding of DSD pathogenesis and ultimately DSD diagnosis and management.
- A 46,XX testicular disorder of sex development caused by a Wilms' tumour Factor-1 (WT1) pathogenic variant(2019) GOMES, Nathalia L.; PAULA, Leila C. P. de; SILVA, Juliana M.; SILVA, Thatiana E.; LERARIO, Antonio M.; NISHI, Mirian Y.; BATISTA, Rafael L.; FARIA JUNIOR, Jose A. D.; MORAES, Daniela; COSTA, Elaine M. F.; HEMESATH, Tatiana P.; GUARAGNA-FILHO, Guilherme; LEITE, Julio C. L.; CARVALHO, Clarissa G.; DOMENICE, Sorahia; COSTA, Eduardo C.; MENDONCA, Berenice B.Molecular diagnosis is rarely established in 46,XX testicular (T) disorder of sex development (DSD) individuals with atypical genitalia. The Wilms' tumour factor-1 (WT1) gene is involved in early gonadal development in both sexes. Classically, WT1 deleterious variants are associated with 46,XY disorders of sex development (DSD) because of gonadal dysgenesis. We report a novel frameshift WT1 variant identified in an SRY-negative 46,XX testicular DSD girl born with atypical genitalia. Target massively parallel sequencing involving DSD-related genes identified a novel heterozygous WT1 c.1453_1456del; p.Arg485Glyfs*14 variant located in the fourth zinc finger of the protein which is absent in the population databases. Segregation analysis and microsatellite analysis confirmed the de novo status of the variant that is predicted to be deleterious by in silico tools and to increase WT1 target activation in crystallographic model. This novel and predicted activating frameshift WT1 variant leading to the 46,XX testicular DSD phenotype includes the fourth zinc-finger DNA-binding domain defects in the genetic aetiology of 46,XX DSD.