LUCIANI RENATA SILVEIRA DE CARVALHO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
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
11 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 11
- An activating mutation in the CRHR1 gene is rarely associated with pituitary-dependent hyperadrenocorticism in poodles(2017) DE-MARCO, Viviani; CARVALHO, Luciani R.; GUZZO, Mariana F.; OLIVEIRA, Paulo S. L.; GOMES, Larissa G.; MENDONCA, Berenice B.OBJECTIVES: Pituitary-dependent hyperadrenocorticism is the most common cause of naturally occurring hypercortisolism in dogs. CRHR1 expression in human and dog corticotrophinomas suggested that this gene affects pituitary tumorigenesis. The present study aimed to investigate mutations in the CRHR1 coding region in poodles with pituitary-dependent hyperadrenocorticism. METHODS: Fifty poodles with pituitary-dependent hyperadrenocorticism and 50 healthy poodles were studied. Genomic DNA was amplified by PCR and analyzed by Sanger sequencing. RESULTS: The novel CRHR1 p.V97M mutation was identified in one dog. This valine residue, located in the amino-terminal extracellular domain, exhibits high affinity for its corticotropin-releasing hormone (CRH) ligand. Bioinformatic analysis revealed structural rearrangements in the mutant protein, with a 17% increase in the surface binding affinity between CRHR1 and CRH. In vitro functional studies showed that mutant CRHR1 induced higher ACTH secretion than the wild type after stimulation with human CRH. CONCLUSION: These results suggest that germline activating mutations in CRHR1 may be a rare cause of pituitary hyperadrenocorticism in poodles.
- Successful Pregnancies After Adequate Hormonal Replacement in Patients With Combined Pituitary Hormone Deficiencies(2017) CORREA, Fernanda A.; BIANCHI, Paulo H. M.; FRANCA, Marcela M.; OTTO, Aline P.; RODRIGUES, Rodrigo J. M.; EJZENBERG, Dani; SERAFINI, Paulo C.; BARACAT, Edmundo Chada; FRANCISCO, Rossana P. V.; BRITO, Vinicius N.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice B.; CARVALHO, Luciani R.Context: Women with hypopituitarism have lower pregnancy rates after ovulation induction. Associated pituitary hormone deficiencies might play a role in this poorer outcome. Objective: We evaluated fertility treatment and pregnancy outcomes in five women with childhoodonset combined pituitary hormone deficiencies (CPHD). Patients and Methods: Five women with CPHD were referred for fertility treatment after adequacy of hormone replacement was determined. Patients were subjected to controlled ovarian stimulation (COS) for timed intercourse, intrauterine insemination, or in vitro fertilization, according to the presence or absence of other infertility factors (male or tubal). Results: All women became pregnant. The number of COS attempts until pregnancy was achieved varied between 1 and 5. The duration of COS resulting in at least one dominant follicle varied between 9 and 28 days, and total gonadotropin consumed varied between 1200 and 3450 IU. Two patients with severely suppressed basal gonadotropin levels since an early age had a cancelled COS cycle. All pregnancies were singleton except one (monochorionic twin gestation). The gestational ages at birth ranged from 35 weeks to 39 weeks and 4 days; three patients underwent cesarean section, and two had vaginal deliveries. Only one newborn was small for gestational age (delivered at 35 weeks). Conclusion: Adequate hormonal replacement prior to ovarian stimulation resulted in successful pregnancies in patients with childhood-onset CPHD, indicating that hormone replacement, including growth hormone, is an important step prior to fertility treatments in these patients.
bookPart Hipopituitarismo em crianças e adultos(2017) CARVALHO, Luciani Renata Silveira de; CHANG, Cláudia Veiga; CORRêA, Fernanda de Azevedo; MADEIRA, João Luiz Oliveira; GUZZO, Mariana Furieri; ARNHOLD, Ivo Jorge Prado- A recurrent synonymous mutation in the human androgen receptor gene causing complete androgen insensitivity syndrome(2017) BATISTA, Rafael Loch; RODRIGUES, Andresa di Santi; NISHI, Mirian Yumie; GOMES, Nathalia Lisboa; FARIA JUNIOR, Jose Antonio Diniz; MORAES, Daniela Rodrigues de; CARVALHO, Luciani Renata; COSTA, Elaine Maria Frade; DOMENICE, Sorahia; MENDONCA, Berenice BilharinhoAndrogen insensitivity syndrome (AIS) is the most common cause of 46,XY disorders of sex development (46,XY DSD). This syndrome is an X-linked inheritance disease and it is caused by mutations in the human androgen receptor (AR) gene. Non-synonymous point AR mutations are frequently described in this disease, including in the complete phenotype. We present a novel synonymous mutation in the human AR gene (c.1530C > T) in four 46,XY patients from two unrelated families associated with complete androgen insensitivity syndrome (CAIS). The analysis of mRNA from testis showed that synonymous AR mutation changed the natural exon 1 donor splice site, with deletion of the last 92 nucleotides of the AR exon 1 leading to a premature stop codon 12 positions ahead resulting in a truncate AR protein. Linkage analyses suggested a probable founder effect for this mutation. In conclusion, we described the first synonymous AR mutation associated with CATS phenotype, reinforcing the disease-causing role of synonymous mutations
- Differential Expression of Stem Cell Markers in Human Adamantinomatous Craniopharyngioma and Pituitary Adenoma(2017) CHANG, Claudia Veiga; ARAUJO, Ricardo Vieira; CIRQUEIRA, Cinthya Santos; CANI, Carolina Maria Gomes; MATUSHITA, Hamilton; CESCATO, Valter Angelo Sperling; FRAGOSO, Maria Candida Barisson Villares; BRONSTEIN, Marcello Delano; ZERBINI, Maria Claudia Nogueira; MENDONCA, Berenice Bilharinho; CARVALHO, Luciani RenataBackground/Aims: Although craniopharyngioma (CP) is histologically benign, it is a pituitary tumour that grows rapidly and often recurs. Adamantinomatous CP (ACP) was associated with an activating mutation in beta-catenin, and it has been postulated that pituitary stem cells might play a role in oncogenesis in human ACP. Stem cells have also been identified in pituitary adenoma. Our aim was to characterize the expression pattern of ABCG2, CD44, DLL4, NANOG, NOTCH2, POU5F1/OCT4, SOX2, and SOX9 stem cell markers in human ACP and pituitary adenoma. Methods and Results: We studied 33 patients (9 ACP and 24 adenoma) using real- time quantitative PCR (RT-qPCR) and immunohistochemistry. SOX9 was up-regulated in ACP, exhibiting positive immunostaining in the epithelium and stroma, with the highest expression in patients with recurrence. CD44 was overexpressed in ACP as confirmed by immunohistochemistry. SOX2 did not significantly differ among the tumour types. The RT-qPCR array showed an increased expression of MKI67, OCT4/POU5F1, and DLL4 in all tumours. NANOG was decreased in ACP. ABCG2 was down-regulated in most of the tumours. NOTCH2 was significantly decreased in the adenomas. Conclusion: Our results confirm the presence of stem cell markers in human pituitary tumours as well as the different expression patterns of ACP and adenoma. These findings suggest that ACP may originate from a more undifferentiated cell cluster. Additionally, SOX9 immunodetection in the stroma and the highest expression levels related to the relapse of patients suggest a contribution to the aggressive behaviour and high recurrence of this tumour type. (C) 2016 S. Karger AG, Basel.
conferenceObject E74 LIKE ETS TRANSCRIPTION FACTOR 4 ( ELF4) IS A CANDIDATE GENE FOR X- LINKED FAMILIAL ISOLATED GROWTH HORMONE DEFICIENCY BY WHOLE EXOME SEQUENCING(2017) CORREA, Fernanda A.; FANG, Qing; LERARIO, Antonio M.; MA, Qianyi; OZEL, Bilge A.; LI, Jun Z.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; ARNHOLD, Ivo J. P.; CAMPER, Sally A.; MENDONCA, Berenice B.conferenceObject MOLECULAR ANALYSIS OF BRAZILIAN PATIENTS WITH COMBINED PITUITARY HORMONE DEFICIENCY (CPHD) AND ORTHOTOPIC POSTERIOR PITUITARY LOBE (OPP) REVEALS 8 DIFFERENT PROP1 ALTERATIONS WITH THREE NOVEL MUTATIONS(2017) MADEIRA, Joao L. O.; NISHI, Mirian Y.; NAKAGUMA, Marilena; BENNEDETTI, Anna F.; BISCOTTO, Isabela P.; FERNANDES, Thamiris; PEQUENO, Thiago; FIGUEIREDO, Thalita; FRANCA, Marcela M.; CORREA, Fernanda A.; OTTO, Aline P.; ABRAO, Milena; MIRAS, Mirta; SANTOS, Silvana; JORGE, Alexander A. L.; COSTALONGA, Everlayny F.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; CARVALHO, Luciani R.- Growth hormone deficiency with advanced bone age: phenotypic interaction between GHRH receptor and CYP21A2 mutations diagnosed by sanger and whole exome sequencing(2017) CORREA, Fernanda A.; FRANCA, Marcela M.; FANG, Qing; MA, Qianyi; BACHEGA, Tania A.; RODRIGUES, Andresa; OZEL, Bilge A.; LI, Jun Z.; MENDONCA, Berenice B.; JORGE, Alexander A. L.; CARVALHO, Luciani R.; CAMPER, Sally A.; ARNHOLD, Ivo J. P.Isolated growth hormone deficiency (IGHD) is the most common pituitary hormone deficiency and, clinically, patients have delayed bone age. High sequence similarity between CYP21A2 gene and CYP21A1P pseudogene poses difficulties for exome sequencing interpretation. A 7.5 year-old boy born to second-degree cousins presented with severe short stature (height SDS -3.7) and bone age of 6 years. Clonidine and combined pituitary stimulation tests revealed GH deficiency. Pituitary MRI was normal. The patient was successfully treated with rGH. Surprisingly, at 10.8 years, his bone age had advanced to 13 years, but physical exam, LH and testosterone levels remained prepubertal. An ACTH stimulation test disclosed a non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency explaining the bone age advancement and, therefore, treatment with cortisone acetate was added. The genetic diagnosis of a homozygous mutation in GHRHR (p.Leu144His), a homozygous CYP21A2 mutation (p.Val282Leu) and CYP21A1P pseudogene duplication was established by Sanger sequencing, MLPA and whole-exome sequencing. We report the unusual clinical presentation of a patient born to consanguineous parents with two recessive endocrine diseases: non-classic congenital adrenal hyperplasia modifying the classical GH deficiency phenotype. We used a method of paired read mapping aided by neighbouring mis-matches to overcome the challenges of exome-sequencing in the presence of a pseudogene.
conferenceObject PARTIAL RECOVERY OF PITUITARY FUNCTION AFTER LINEAR GROWTH IN PATIENTS WITH CONGENITAL COMBINED PITUITARY HORMONE DEFICIENCY (CPHD)(2017) MADEIRA, Joao L. O.; BISCOTTO, Isabela P.; CORREA, Fernanda A.; OTTO, Aline P.; COSTALONGA, Everlayny F.; FRANCA, Marcela M.; JORGE, Alexander; ARNHOLD, Ivo J.; MENDONCA, Berenice B.; CARVALHO, Luciani R.- Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations(2017) MADEIRA, Joao Lo; NISHI, Mirian Y.; NAKAGUMA, Marilena; BENEDETTI, Anna F.; BISCOTTO, Isabela Peixoto; FERNANDES, Thamiris; PEQUENO, Thiago; FIGUEIREDO, Thalita; FRANCA, Marcela M.; CORREA, Fernanda A.; OTTO, Aline P.; ABRAO, Milena; MIRAS, Mirta B.; SANTOS, Silvana; JORGE, Alexander A. L.; COSTALONGA, Everlayny F.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; CARVALHO, Luciani R.BackgroundMutations in PROP1, HESX1 and LHX3 are associated with combined pituitary hormone deficiency (CPHD) and orthotopic posterior pituitary lobe (OPP). ObjectiveTo identify mutations in PROP1, HESX1 and LHX3 in a large cohort of patients with CPHD and OPP (35 Brazilian, two Argentinian). Design and MethodsWe studied 23 index patients with CPHD and OPP (six familial and 17 sporadic) as well as 14 relatives. PROP1 was sequenced by the Sanger method in all except one sporadic case studied using a candidate gene panel. Multiplex ligation-dependent probe amplification (MLPA) was applied to one familial case in whom PROP1 failed to amplify by PCR. In the 13 patients without PROP1 mutations, HESX1 and LHX3 were sequenced by the Sanger method. ResultsWe identified PROP1 mutations in 10 index cases. Three mutations were novel: one affecting the initiation codon (c.1A>G) and two affecting splicing sites, c.109+1G>A and c.342+1G>C. The known mutations, c.150delA (p.Arg53Aspfs*112), c.218G>A (p.Arg73His), c.263T>C (p.Phe88Ser) and c.301_302delAG (p.Leu102Cysfs*8), were also detected. MLPA confirmed complete PROP1 deletion in one family. We did not identify HESX1 and LHX3 mutations by Sanger. ConclusionPROP1 mutations are a prevalent cause of congenital CPHD with OPP, and therefore, PROP1 sequencing must be the first step of molecular investigation in patients with CPHD and OPP, especially in populations with a high frequency of PROP1 mutations. In the absence of mutations, massively parallel sequencing is a promising approach. The high prevalence and diversity of PROP1 mutations is associated with the ethnic background of this cohort.