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
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conferenceObject Prospective Genetic Analysis of Patients with Congenital Growth Hormone Deficiency by Massive Parallel Sequencing Using Target Gene Panel(2016) NAKAGUMA, M.; JORGE, A. Augusto de Lima; FUNARI, M. Ferreira de Assis; LERARIO, Marcondes A.; CARVALHO, L. Renata Silveira de; MENDONCA, B. Bilharinho de; ARNHOLD, I Jorge Prado- HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype(2016) FANG, Qing; BENEDETTI, Anna Flavia Figueredo; MA, Qianyi; GREGORY, Louise; LI, Jun Z.; DATTANI, Mehul; SADEGHI-NEJAD, Abdollah; ARNHOLD, Ivo J. P.; MENDONCA, Berenice Bilharinho; CAMPER, Sally A.; CARVALHO, Luciani R.IntroductionMutations in the transcription factor HESX1 can cause isolated growth hormone deficiency (IGHD) or combined pituitary hormone deficiency (CPHD) with or without septo-optic dysplasia (SOD). So far there is no clear genotype-phenotype correlation. Patients and ResultsWe report four different recessive loss-of-function mutations in three unrelated families with CPHD and no midline defects or SOD. A homozygous p.R160C mutation was found by Sanger sequencing in two siblings from a consanguineous family. These patients presented with ACTH, TSH and GH deficiencies, severe anterior pituitary hypoplasia (APH) or pituitary aplasia (PA) and normal posterior pituitary. The p.R160C mutation was previously reported in a case with SOD, CPHD and ectopic posterior pituitary (EPP). Using exome sequencing, a homozygous p.I26T mutation was found in a Brazilian patient born to consanguineous parents. This patient had evolving CPHD, normal ACTH, APH and normal posterior pituitary (NPP). A previously reported patient homozygous for p.I26T had evolving CPHD and EPP. Finally, we identified compound heterozygous mutations in HESX1, p.[R159W];[R160H], in a patient with PA and CPHD. We showed that both of these mutations abrogate the ability of HESX1 to repress PROP1-mediated transcriptional activation. A patient homozygous for p.R160H was previously reported in a patient with CPHD, EPP, APH. ConclusionThese three examples demonstrate that HESX1 mutations cause variable clinical features in patients, which suggests an influence of modifier genes or environmental factors on the phenotype.
conferenceObject Fertility and Pregnancy Outcomes after Ovarian Stimulation in Five Patients with Congenital Hypopituitarism Treated with GH Since Childhood(2016) CORREA, F. A.; BIANCHI, P. H. M.; FRANCA, M. M.; OTTO, A. P.; RODRIGUES, R. J. M.; I, D. Ejzenberg; SERAFINI, P. C.; ARNHOLD, I. J. P.; MENDONCA, B. B.; CARVALHO, L. R. S.conferenceObject Isolated Growth Hormone Deficiency with Advanced Bone Age: Phenotypic Interaction between GHRH Receptor and CYP21A2 Mutations Diagnosed by Sanger and Whole Exome Sequencing(2016) CORREA, F. A.; FRANCA, M. M.; FANG, Q.; MA, Q.; OZEL, B. A.; BACHEGA, T. A.; RODRIGUES, A.; LI, J. Z.; MENDONCA, B. B.; JORGE, A. A. L.; CARVALHO, L. R.; CAMPER, S. A.; ARNHOLD, I. J. P.bookPart Hipopituitarismo(2016) CARVALHO, Luciani Renata Silveira de; JALLAD, Raquel Soares; ARNHOLD, Ivo Jorge Prado- A homozygous point mutation in the GH1 promoter (c.-223C > T) leads to reduced GH1 expression in siblings with isolated GH deficiency (IGHD)(2016) MADEIRA, Joao L. O.; JORGE, Alexander A. L.; MARTIN, Regina M.; MONTENEGRO, Luciana R.; FRANCA, Marcela M.; COSTALONGA, Everlayny F.; CORREA, Fernanda A.; OTTO, Aline P.; ARNHOLD, Ivo J. P.; FREITAS, Helayne S.; MACHADO, Ubiratan F.; MENDONCA, Berenice B.; CARVALHO, Luciani R.Context: Mutations in the GH1 promoter are a rare cause of isolated growth hormone deficiency (IGHD). Objective: To identify the molecular aetiology of a family with IGHD. Design: DNA sequencing, electromobility shift (EMSA) and luciferase reporter assays. Setting: University Hospital. Patients: Three siblings (2M) born to consanguineous parents presented with IGHD with normal pituitary on MRI. Methods: The GH1 proximal promoter, locus control region, five exons and four introns as well as GHRHR gene were sequenced in genomic DNA by Sanger method. DNA- protein interaction was evaluated by EMSA in nuclear extracts of GH3 pituitary cells. Dual-luciferase reporter assays were performed in cells transiently transfected with plasmids containing four different combinations of GH1 allelic variants (AV). Results: The patients harboured two homozygous variants (c.-185T>C and c.-223C>T) in the GH1 promoter within a highly conserved region and predicted binding sites for POU1F1/SP1 and SP1 respectively. The parents and brother were carriers and these variants were absent in 100 controls. EMSA demonstrated absent binding of GH3 nuclear extract to the c.-223C>T variant and normal binding of both POU1F1 protein and GH3 nuclear extract to the c.-185T>C variant. In contrast to GH1 promoter with AV only at c.-185, the GH1 promoter containing the AV only at c.-223 and at both positions drove significantly less expression of luciferase compared with the promoter containing either positions wild type in luciferase reporter assays. Conclusion: To our knowledge, c.-223C>T is the first homozygous point mutation in the GH1 promoter that leads to short stature due to IGHD.
conferenceObject Genetic Diagnosis of Congenital Growth Hormone Deficiency by Massive Parallel Sequencing Using a Target Gene Panel(2016) NAKAGUMA, Marilena; JORGE, Alexander Augusto de Lima; FUNARI, Mariana Ferreira de Assis; LERARIO, Antonio Marcondes; CORREAA, Fernanda de Azevedo; CARVALHOA, Luciani Renata Silveira de; MENDONCA, Berenice Bilharinho de; ARNHOLD, Ivo Jorge Prado