MIRIAN YUMIE NISHI
Projetos de Pesquisa
Unidades Organizacionais
LIM/42 - Laboratório de Hormônios e Genética Molecular, Hospital das Clínicas, Faculdade de Medicina
11 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 11
conferenceObject Inherited Digenic Missense Variants in FGFR2 and MAP3K1 Genes in Two Siblings with 46,XY Partial Gonadal Dysgenesis(2014) MACHADO, Aline Zamboni; NISHI, Mirian Yumie; COSTA, Elaine Maria Frade; MENDONCA, Berenice B.; DOMENICE, Sorahia- Homozygous Inactivating Mutation in NANOS3 in Two Sisters with Primary Ovarian Insufficiency(2014) SANTOS, Mariza G.; MACHADO, Aline Z.; MARTINS, Conceicao N.; DOMENICE, Sorahia; COSTA, Elaine M. F.; NISHI, Mirian Y.; FERRAZ-DE-SOUZA, Bruno; JORGE, Soraia A. C.; PEREIRA, Carlos A.; SOARDI, Fernanda C.; MELLO, Maricilda P. de; MACIEL-GUERRA, Andrea T.; GUERRA-JUNIOR, Gil; MENDONCA, Berenice B.Despite the increasing understanding of female reproduction, the molecular diagnosis of primary ovarian insufficiency (POI) is seldom obtained. The RNA-binding protein NANOS3 poses as an interesting candidate gene for POI since members of the Nanos family have an evolutionarily conserved function in germ cell development and maintenance by repressing apoptosis. We performed mutational analysis of NANOS3 in a cohort of 85 Brazilian women with familial or isolated POI, presenting with primary or secondary amenorrhea, and in ethnically-matched control women. A homozygous p.Glu120Lysmutation in NANOS3 was identified in two sisters with primary amenorrhea. The substituted amino acid is located within the second C2HC motif in the conserved zinc finger domain of NANOS3 and in silico molecular modelling suggests destabilization of protein-RNA interaction. In vitro analyses of apoptosis through flow cytometry and confocal microscopy show that NANOS3 capacity to prevent apoptosis was impaired by this mutation. The identification of an inactivating missense mutation in NANOS3 suggests a mechanism for POI involving increased primordial germ cells (PGCs) apoptosis during embryonic cell migration and highlights the importance of NANOS proteins in human ovarian biology.
- Amplification of the Insulin-Like Growth Factor 1 Receptor Gene Is a Rare Event in Adrenocortical Adenocarcinomas: Searching for Potential Mechanisms of Overexpression(2014) RIBEIRO, Tamaya Castro; JORGE, Alexander Augusto; ALMEIDA, Madson Q.; MARIANI, Beatriz Marinho de Paula; NISHI, Mirian Yumi; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson Villares; LATRONICO, Ana ClaudiaContext. IGF1R overexpression appears to be a prognostic biomarker of metastatic pediatric adrenocortical tumors. However, the molecular mechanisms that are implicated in its upregulation remain unknown. Aim. To investigate the potential mechanisms involved in IGF1R overexpression. Patients and Methods. We studied 64 adrenocortical tumors. IGF1R copy number variation was determined in all patients using MLPA and confirmed using real time PCR. In a subgroup of 32 patients, automatic sequencing was used to identify IGF1R allelic variants and the expression of microRNAs involved in IGF1R regulation by real time PCR. Results. IGF1R amplification was detected in an adrenocortical carcinoma that was diagnosed in a 46-year-old woman with Cushing's syndrome and virilization. IGF1R overexpression was demonstrated in this case. In addition, gene amplification of other loci was identified in this adrenocortical malignant tumor, but no IGF1R copy number variation was evidenced in the remaining cases. Automatic sequencing revealed three known polymorphisms but they did not correlate with its expression. Expression of miR-100, miR-145, miR-375, and miR-126 did not correlate with IGF1R expression. Conclusion. We demonstrated amplification and overexpression of IGF1R gene in only one adrenocortical carcinoma, suggesting that these combined events are uncommon. In addition, IGF1R polymorphisms and abnormal microRNA expression did not correlate with IGF1R upregulation in adrenocortical tumors.
conferenceObject Analysis of GNAS Defects in 28 Patients with Pseudohypoparathyroidism or Pseudopseudohypoparathyroidism and Correlation with the Phenotype(2014) REIS, Mariana Tenorio Antunes; FERRAZ-DE-SOUZA, Bruno; NISHI, Mirian Yumie; AYAKIAN, Amaryllis; CORREA, Pedro Henrique S.; MARTIN, Regina M.- Autosomal recessive form of isolated growth hormone deficiency is more frequent than the autosomal dominant form in a Brazilian cohort(2014) LIDO, Andria C. V.; FRANCA, Marcela M.; CORREA, Fernanda A.; OTTO, Aline P.; CARVALHO, Luciani R.; QUEDAS, Elisangela P. S.; NISHI, Mirian Y.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Background: In most studies, the autosomal dominant (type II) form of isolated growth hormone deficiency (IGHD) has been more frequent than the autosomal recessive (type I) form. Our aim was to assess defects in the GH1 in short Brazilian children with different GH secretion status. Subjects and methods: We selected 135 children with postnatal short stature and classified according to the highest GH peak at stimulation tests in: severe IGHD (peak GH <= 3.3 mu g/L, n = 38, all with normal pituitary magnetic resonance imaging); GH peak between 3.3 and 10 mu g/L (n = 76); and GH peak >10 mu g/L (n = 21). The entire coding region of GH1 was sequenced and complete GH1 deletions were assessed by Multiplex Ligation Dependent Probe Amplification and restriction enzyme digestion. Results: Patients with severe IGHD had a higher frequency of consanguinity, were shorter, had lower levels of IGF-1 and IGFBP-3, and despite treatment with lower GH doses had a greater growth response than patients with GH peak >= 3.3 mu g/L. Mutations were found only in patients with severe IGHD (GH peak <3.3 mu g/L). Eight patients had autosomal recessive IGHD: Seven patients were homozygous for GH1 deletions and one patient was compound heterozygous for a GH1 deletion and the novel c.171 + 5G>C point mutation in intron 2, predicted to abolish the donor splice site. Only one patient, who was heterozygous for the c.291 + 1G>T mutation located at the universal donor splice site of intron 3 and predicts exon 3 skipping, had an autosomal dominant form. Conclusion: Analysis of GH1 in a cohort of Brazilian patients revealed that the autosomal recessive form of IGHD was more common than the dominant one, and both were found only in severe IGHD.
conferenceObject Genotype/ Hormonal Phenotype Mismatch in the Diagnosis of 17 a Hydroxysteroid 3 Dehydrogenase Deficiency(2014) KHATTAB, Ahmed; YAU, Mabel; DOMENICE, Sorahia; MUHURI, Dwaipayan; COSTA, Elaine Maria Frade; YUEN, Tony; PINA, Christian Enrique; NISHI, Mirian Yumie; YANG, Amy C.; MENDONCA, Berenice B.; NEW, Maria I.- 46,XY DSD due to 17 Beta-Hydroxysteroid Dehydrogenase Type 3 Deficiency(2014) MENDONCA, Berenice B.; COSTA, Elaine M.F.; INACIO, Marlene; OLIVEIRA JUNIOR, Ari A.; MARTIN, Regina M.; NISHI, Mirian Y.; MACHADO, Aline Z.; CARVALHO, Filomena Marino; DENES, Francisco Tibor; DOMENICE, Sorahia17beta-hydroxysteroid dehydrogenase 3 deficiency (17beta-HSD3) consists of a defect in the last phase of steroidogenesis, in which androstenedione is converted into testosterone and estrone into estradiol. Patients present female-like or with ambiguous genitalia at birth and most affected males are raised as females. Virilization in subjects with 17beta-HSD3 deficiency occurs at the time of puberty and almost half change to be males. Maintenance of the testes in patients raised male is safe and recommended, except when the testes cannot be positioned inside the scrotum. The phenotype of 46,XY disorders of sex development (DSD) owing to 17beta-HSD3 deficiency is extremely variable and is clinically indistinguishable from other causes of 46,XY DSD such as partial androgen insensitivity syndrome and 5alfa-reductase 2 deficiency. Laboratory diagnosis is based on elevated serum levels of androstenedione and estrone and low levels of testosterone and estradiol, resulting in elevated androstenedione:testosterone and estrone:estradiol ratios, indicating an impairment of the conversion of 17-keto into 17-hydroxysteroids. The disorder is due to homozygous or compound heterozygous mutations in the HSD17B3 gene that encodes the 17beta-HSD3 isoenzyme. Molecular genetic testing confirms the diagnosis and provides the orientation for genetic counseling. Our proposal in this article is to review the reported and our own cases of 17beta-HSD3 deficiency.
conferenceObject Amplification of the Insulin-like Growth Factor 1 Receptor Gene in an Adrenocortical Adenocarcinoma: Searching for Potential Mechanisms of Overexpression(2014) RIBEIRO, Tamaya C.; JORGE, Alexander Augusto Lima; ALMEIDA, Madson Q.; MARIANI, Beatriz M. P.; NISHI, Mirian Yumie; MENDONCA, Berenice B.; FRAGOSO, Maria Candida Barisson Villares; LATRONICO, Ana ClaudiaconferenceObject High Frequency of Subclinical Cushing's Syndrome in the Inherited Autosomal Dominant Primary Macronodular Adrenal Hyperplasia Due to ARMC5 Mutations(2014) ALENCAR, Guilherme Asmar; ALMEIDA, Madson Q.; LERARIO, Antonio Marcondes; RESENDE, Gabriela; NISHI, Mirian Yumie; PEREIRA, Maria Adelaide Albergaria; MENDONCA, Berenice B.; FRAGOSO, Maria Candida B. V.- ARMC5 Mutations Are a Frequent Cause of Primary Macronodular Adrenal Hyperplasia(2014) ALENCAR, Guilherme Asmar; LERARIO, Antonio Marcondes; NISHI, Mirian Yumie; MARIANI, Beatriz Marinho de Paula; ALMEIDA, Madson Queiroz; TREMBLAY, Johanne; HAMET, Pavel; BOURDEAU, Isabelle; ZERBINI, Maria Claudia Nogueira; PEREIRA, Maria Adelaide Albergaria; GOMES, Gilberto Carlos; ROCHA, Manoel de Souza; CHAMBO, Jose Luis; LACROIX, Andre; MENDONCA, Berenice Bilharinho; FRAGOSO, Maria Candida Barisson VillaresContext: Primary macronodular adrenal hyperplasia (PMAH) is a rare cause of Cushing's syndrome, usually characterized by functioning adrenal macronodules and increased cortisol production. Familial clustering of PMAH has been described, suggesting an inherited genetic cause for this condition. Objective: The aim of the present study was to identify the gene responsible for familial PMAH. Patients and Methods: Forty-seven individuals of a Brazilian family with PMAH were evaluated. A single-nucleotide polymorphism-based genome-wide linkage analysis followed by whole-exome sequencing were then performed in selected family members. Additionally, 29 other patients with PMAH and 125 randomly selected healthy individuals were studied to validate the genetic findings. Moreover, PMAH tissue was also analyzed through whole-exome sequencing, conventional sequencing, and microsatellite analysis. Results: A heterozygous germline variant in the ARMC5 gene (p.Leu365Pro) was identified by whole-exome sequencing in a candidate genomic region (16p11.2). Subsequently, the same variant was confirmed by conventional sequencing in all 16 affected family members. The variant was predicted to be damaging by in silico methods and was not found in available online databases or in the 125 selected healthy individuals. Seven additional ARMC5 variants were subsequently identified in 5 of 21 patients with apparently sporadic PMAH and in 2 of 3 families with the disease. Further molecular analysis identified a somatic mutational event in 4 patients whose adrenal tissue was available. Conclusions: Inherited autosomal dominant mutations in the ARMC5 gene are a frequent cause of PMAH. Biallelic inactivation of ARMC5 is consistent with its role as a potential tumor suppressor gene.