RENATA DA CUNHA SCALCO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
LIM/25 - Laboratório de Endocrinologia Celular e Molecular, Hospital das Clínicas, Faculdade de Medicina
22 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 22
- STAT5B mutations in heterozygous state have negative impact on height: another clue in human stature heritability(2015) SCALCO, Renata C.; HWA, Vivian; DOMENE, Horacio M.; JASPER, Hector G.; BELGOROSKY, Alicia; MARINO, Roxana; PEREIRA, Alberto M.; TONELLI, Carlos A.; WIT, Jan M.; ROSENFELD, Ron G.; JORGE, Alexander A. L.Context and objective: GH insensitivity with immune dysfunction caused by STAT5B mutations is an autosomal recessive condition. Heterozygous mutations in other genes involved in growth regulation were previously associated with a mild height reduction. Our objective was to assess for the first time the phenotype of heterozygous STAT5B mutations. Methods: We genotyped and performed clinical and laboratory evaluations in 52 relatives of two previously described Brazilian brothers with homozygous STAT5B c.424_427del mutation (21 heterozygous). Additionally, we obtained height data and genotype from 1104 adult control individuals from the same region in Brazil and identified five additional families harboring the same mutation (18 individuals, 11 heterozygous). Furthermore, we gathered the available height data from first-degree relatives of patients with homozygous STAT5B mutations (17 individuals from seven families). Data from heterozygous individuals and non-carriers were compared. Results: Individuals carrying heterozygous STAT5B c.424_427del mutation were 0.6 SDS shorter than their non-carrier relatives (P=0.009). Heterozygous subjects also had significantly lower SDS for serum concentrations of IGF1 (P=0.028) and IGFBP3 (P=0.02) than their non-carrier relatives. The 17 heterozygous first-degree relatives of patients carrying homozygous STAT5B mutations had an average height SDS of -1.4 +/- 0.8 when compared with population-matched controls (P<0.001). Conclusions: STAT5B mutations in the heterozygous state have a significant negative impact on height (similar to 3.9 cm). This effect is milder than the effect seen in the homozygous state, with height usually within the normal range. Our results support the hypothesis that heterozygosity of rare pathogenic variants contributes to normal height heritability.
- Genetic Predictors of Long-Term Response to Growth Hormone (GH) Therapy in Children With GH Deficiency and Turner Syndrome: The Influence of a SOCS2 Polymorphism(2014) BRAZ, Adriana F.; COSTALONGA, Everlayny F.; TRARBACH, Ericka B.; SCALCO, Renata C.; MALAQUIAS, Alexsandra C.; GUERRA-JUNIOR, Gil; ANTONINI, Sonir R. R.; MENDONCA, Berenice B.; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.Background: There is great interindividual variability in the response to GH therapy. Ascertaining genetic factors can improve the accuracy of growth response predictions. Suppressor of cytokine signaling (SOCS)-2 is an intracellular negative regulator of GH receptor (GHR) signaling. Objective: The objective of the study was to assess the influence of a SOCS2 polymorphism (rs3782415) and its interactive effect with GHR exon 3 and -202 A/C IGFBP3 (rs2854744) polymorphisms on adult height of patients treated with recombinant human GH (rhGH). Design and Patients: Genotypes were correlated with adult height data of 65 Turner syndrome (TS) and 47 GH deficiency (GHD) patients treated with rhGH, by multiple linear regressions. Generalized multifactor dimensionality reduction was used to evaluate gene-gene interactions. Results: Baseline clinical data were indistinguishable among patients with different genotypes. Adult height SD scores of patients with at least one SOCS2 single-nucleotide polymorphism rs3782415-C were 0.7 higher than those homozygous for the T allele (P < .001). SOCS2 (P < .003), GHR-exon 3 (P = .016) and -202 A/C IGFBP3 (P = .013) polymorphisms, together with clinical factors accounted for 58% of the variability in adult height and 82% of the total height SD score gain. Patients harboring any two negative genotypes in these three different loci (homozygosity for SOCS2 T allele; the GHR exon 3 full-length allele and/or the -202C-IGFBP3 allele) were more likely to achieve an adult height at the lower quartile (odds ratio of 13.3; 95% confidence interval of 3.2-54.2, P = .0001). Conclusion: The SOCS2 polymorphism (rs3782415) has an influence on the adult height of children with TS and GHD after long-term rhGH therapy. Polymorphisms located in GHR, IGFBP3, and SOCS2 loci have an influence on the growth outcomes of TS and GHD patients treated with rhGH. The use of these genetic markers could identify among rhGH-treated patients those who are genetically predisposed to have less favorable outcomes.
- Diagnostic yield of a multigene sequencing approach in children classified as idiopathic short stature(2022) ANDRADE, Nathalia Liberatoscioli Menezes; FUNARI, Mariana Ferreira de Assis; MALAQUIAS, Alexsandra Christianne; COLLETT-SOLBERG, Paulo Ferrez; GOMES, Nathalia L. R. A.; SCALCO, Renata; DANTAS, Naiara Castelo Branco; REZENDE, Raissa C.; TIBURCIO, Angelica M. F. P.; SOUZA, Micheline A. R.; FREIRE, Bruna L.; V, Ana C. Krepischi; LONGUI, Carlos Alberto; LERARIO, Antonio Marcondes; ARNHOLD, Ivo J. P.; JORGE, Alexander A. L.; VASQUES, Gabriela AndradeObjectiveMost children with short stature remain without an etiologic diagnosis after extensive clinical and laboratory evaluation and are classified as idiopathic short stature (ISS). This study aimed to determine the diagnostic yield of a multigene analysis in children classified as ISS. Design and methodsWe selected 102 children with ISS and performed the genetic analysis as part of the initial investigation. We developed customized targeted panel sequencing, including all genes already implicated in the isolated short-stature phenotype. Rare and deleterious single nucleotide or copy number variants were assessed by bioinformatic tools. ResultsWe identified 20 heterozygous pathogenic (P) or likely pathogenic (LP) genetic variants in 17 of 102 patients (diagnostic yield = 16.7%). Three patients had more than one P/LP genetic alteration. Most of the findings were in genes associated with the growth plate differentiation: IHH (n = 4), SHOX (n = 3), FGFR3 (n = 2), NPR2 (n = 2), ACAN (n = 2), and COL2A1 (n = 1) or involved in the RAS/MAPK pathway: NF1 (n = 2), PTPN11 (n = 1), CBL (n = 1), and BRAF (n = 1). None of these patients had clinical findings to guide a candidate gene approach. The diagnostic yield was higher among children with severe short stature (35% vs 12.2% for height SDS <= or > -3; P = 0.034). The genetic diagnosis had an impact on clinical management for four children. ConclusionA multigene sequencing approach can determine the genetic etiology of short stature in up to one in six children with ISS, removing the term idiopathic from their clinical classification.
conferenceObject Characterization of Pediatric Chronic Lung Disease Caused by Mutations in Signal Transducer and Activator of Transcription 5B (STAT5B)(2020) FOLEY, C.; SCALCO, R.; KUMAR, A.; TOWE, C.; SRIDHARAN, A.; TRAPNELL, B. C.; WHITSETT, J. A.; WIKENHEISER-BROKAMP, K. A.; JORGE, A.; HWA, V.- Deficiência da STAT5B : uma nova síndrome de insensibilidade ao hormônio de crescimento associada a acometimento imunológico(2013) SCALCO, Renata C.; PUGLIESE-PIRES, Patricia N.; JORGE, Alexander A. L.A new presentation of growth hormone insensitivity (GHI) caused by homozygous mutations in STAT5B (signal transducer and activator of transcription 5B) gene has been characterized in the last years. Its particularity is the association with severe immune dysfunction, especially with lymphocytic interstitial pneumonitis. This may mislead physicians into considering short stature as secondary to chronic immunological disease and consequently into underdiagnosing this form of GHI. The objective of this review is to propagate current knowledge about this rare pathology, facilitating the diagnosis of patients with GHI due to STAT5B mutations in endocrinology and other specialties clinics. Arq Bras Endocrinol Metab. 2013;57(5):333-8
- Differentiating the roles of STAT5B and STAT5A in human CD4(+) T cells(2013) JENKS, Jennifer A.; SEKI, Scott; KANAI, Takahiro; HUANG, Jennifer; MORGAN, Alexander A.; SCALCO, Renata C.; NATH, Ruhi; BUCAYU, Robert; WIT, Jan M.; AL-HERZ, Waleed; RAMADAN, Dina; JORGE, Alexander A.; BACCHETTA, Rosa; HWA, Vivian; ROSENFELD, Ron; NADEAU, Kari C.STAT5A and STAT5B are highly homologous proteins whose distinctive roles in human immunity remain unclear. However, STAT5A sufficiency cannot compensate for STAT5B defects, and human STAT5B deficiency, a rare autosomal recessive primary immunodeficiency, is characterized by chronic lung disease, growth failure and autoimmunity associated with regulatory T cell (Treg) reduction. We therefore hypothesized that STAT5A and STAT5B play unique roles in CD4(+) T cells. Upon knocking down STAT5A or STAT5B in human primary T cells, we found differentially regulated expression of FOXP3 and IL-2R in STAT5B knockdown T cells and down-regulated Bcl-X only in STAT5A knockdown T cells. Functional ex vivo studies in homozygous STAT5B-deficient patients showed reduced FOXP3 expression with impaired regulatory function of STAT5B-null Treg cells, also of increased memory phenotype. These results indicate that STAT5B and STAT5A act partly as non-redundant transcription factors and that STAT5B is more critical for Treg maintenance and function in humans.
conferenceObject FIREFISH Part 2: Efficacy and Safety of Risdiplam (RG7916) in Infants with Type 1 Spinal Muscular Atrophy (SMA)(2020) SERVAIS, Laurent; BARANELLO, Giovanni; MASSON, Riccardo; MAZURKIEWICZ-BELDZINSKA, Maria; ROSE, Kristy; VLODAVETS, Dmitry; XIONG, Hui; ZANOTELI, Edmar; EL-KHAIRI, Muna; FUERST-RECKTENWALD, Sabine; GERBER, Marianne; GORNI, Ksenija; KLETZL, Heidemarie; SCALCO, Renata; DARRAS, Basil T.conferenceObject Evidence for a Founder Effect of C.424_427del STAT5B Mutation Causing Growth Hormone Insensitivity in the South of Brazil(2014) SCALCO, Renata Da Cunha; FUNARI, Mariana Ferreira de Assis; ARACAVA, Rosana Midori; TONELLI, Carlos Andre; JORGE, Alexander Augusto LimaconferenceObject FIREFISH Part 2: 24-month Efficacy and Safety of Risdiplam in Infants with Type 1 Spinal Muscular Atrophy (SMA)(2021) DARRAS, Basil T.; MASSON, Ricardo z; MAZURKIEWICZ-BELDZINSKA, Maria; ROSE, Kristy; XIONG, Hui; ZANOTELI, Edmar; BARANELLO, Giovanni; VLODAVETS, Dmitry; DODMAN, Angela; EL-KHAIRI, Muna; GERBER, Marianne; GORNI, Ksenija; KLETZL, Heidemarie; SCALCO, Renata S.; SERVAIS, LaurentbookPart Baixa estatura desproporcional por mutações no gene SHOX(2012) FUNARI, Mariana; SCALCO, Renata da Cunha; MENDONçA, Berenice Bilharinho de; JORGE, Alexander Augusto de Lima; NISHI, Mirian Yumiee
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