MANUELA GIULIANI MARCONDES ROCHA BRAZ
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
11 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 11
- The molecular landscape of osteogenesis imperfecta in a Brazilian tertiary service cohort(2020) FERNANDES, A. M.; ROCHA-BRAZ, M. G. M.; FRANCA, M. M.; LERARIO, A. M.; SIMOES, V. R. F.; ZANARDO, E. A.; KULIKOWSKI, L. D.; MARTIN, R. M.; MENDONCA, B. B.; FERRAZ-DE-SOUZA, B.We have sought the molecular diagnosis of OI in 38 Brazilian cases through targeted sequencing of 15 candidate genes. While 71% had type 1 collagen-related OI, defects in FKBP10, PLOD2 and SERPINF1, and a potential digenic P3H1/WNT1 interaction were prominent causes of OI in this underrepresented population. Introduction Defects in type 1 collagen reportedly account for 85-90% of osteogenesis imperfecta (OI) cases, but most available molecular data has derived from Sanger sequencing-based approaches in developed countries. Massively parallel sequencing (MPS) allows for systematic and comprehensive analysis of OI genes simultaneously. Our objective was to obtain the molecular diagnosis of OI in a single Brazilian tertiary center cohort. Methods Forty-nine individuals (84% adults) with a clinical diagnosis of OI, corresponding to 30 sporadic and 8 familial cases, were studied. Sixty-three percent had moderate to severe OI, and consanguinity was common (26%). Coding regions and 25-bp boundaries of 15 OI genes (COL1A1, COL1A2, IFITM5 [plus 5 ' UTR], SERPINF1, CRTAP, P3H1, PPIB, SERPINH1, FKBP10, PLOD2, BMP1, SP7, TMEM38B, WNT1, CREB3L1) were analyzed by targeted MPS and variants of interest were confirmed by Sanger sequencing or SNP array. Results A molecular diagnosis was obtained in 97% of cases. COL1A1/COL1A2 variants were identified in 71%, whereas 26% had variants in other genes, predominantly FKBP10, PLOD2, and SERPINF1. A potential digenic interaction involving P3H1 and WNT1 was identified in one case. Phenotypic variability with collagen defects could not be explained by evident modifying variants. Four consanguineous cases were associated to heterozygous COL1A1/COL1A2 variants, and two nonconsanguineous cases had compound PLOD2 heterozygosity. Conclusions Novel disease-causing variants were identified in 29%, and a higher proportion of non-collagen defects was seen. Obtaining a precise diagnosis of OI in underrepresented populations allows expanding our understanding of its molecular landscape, potentially leading to improved personalized care in the future.
bookPart Doenças osteometabólicas(2017) BRAZ, Manuela Giuliani Marcondes RochabookPart Fármacos que afetama homeostasia mineral óssea(2021) BRAZ, Manuela Giuliani Marcondes Rocha; SOUZA, Bruno Ferraz de- Genetics of osteoporosis: searching for candidate genes for bone fragility(2016) ROCHA-BRAZ, Manuela G. M.; FERRAZ-DE-SOUZA, BrunoABSTRACT The pathogenesis of osteoporosis, a common disease with great morbidity and mortality, comprises environmental and genetic factors. As with other complex disorders, the genetic basis of osteoporosis has been difficult to identify. Nevertheless, several approaches have been undertaken in the past decades in order to identify candidate genes for bone fragility, including the study of rare monogenic syndromes with striking bone phenotypes (e.g. osteogenesis imperfecta and osteopetroses), the analysis of individuals or families with extreme osteoporotic phenotypes (e.g. idiopathic juvenile and pregnancy-related osteoporosis), and, chiefly, genome-wide association studies (GWAS) in large populations. Altogether, these efforts have greatly increased the understanding of molecular mechanisms behind bone remodelling, which has rapidly translated into the development of novel therapeutic strategies, exemplified by the tales of cathepsin K (CTSK) and sclerostin (SOST). Additional biological evidence of involvement in bone physiology still lacks for several candidate genes arisen from GWAS, opening an opportunity for the discovery of new mechanisms regulating bone strength, particularly with the advent of high-throughput genomic technologies. In this review, candidate genes for bone fragility will be presented in comprehensive tables and discussed with regard to how their association with osteoporosis emerged, highlighting key players such as LRP5, WNT1 and PLS3. Current limitations in our understanding of the genetic contribution to osteoporosis, such as yet unidentified genetic modifiers, may be overcome in the near future with better genotypic and phenotypic characterisation of large populations and the detailed study of candidate genes in informative individuals with marked phenotype.
conferenceObject High Diagnostic Yield and Higher Proportion of Non-Collagen Defects in Adults with Osteogenesis Imperfecta Analyzed Using Targeted Massively Parallel Sequencing.(2017) FERNANDES, Adriana M.; ROCHA-BRAZ, Manuela G. M.; FRANCA, Monica M.; MARTIN, Regina M.; LERARIO, Antonio M.; MENDONCA, Berenice B.; FERRAZ-DE-SOUZA, BrunoconferenceObject Predictors of Bone Mass Recovery Following Cure of Primary Hyperparathyroidism: 1-Year Follow-Up of 49 cases(2013) FERRAZ-DE-SOUZA, Bruno; MARTIN, Regina M.; ROCHA-BRAZ, Manuela G. M.; FERNANDES, Adriana M.; CORREA, Pedro HenriquebookPart Doenças osteometabólicas(2023) BRAZ, Manuela Giuliani Marcondes RochabookPart Doenças osteometabólicas(2015) BRAZ, Manuela Giuliani Marcondes Rocha- Comprehensive Genetic Analysis of 128 Candidate Genes in a Cohort With Idiopathic, Severe, or Familial Osteoporosis(2020) ROCHA-BRAZ, Manuela G. M.; FRANCA, Monica M.; FERNANDES, Adriana M.; LERARIO, Antonio M.; ZANARDO, Evelin A.; SANTANA, Lucas S. de; KULIKOWSKI, Leslie D.; MARTIN, Regina M.; MENDONCA, Berenice B.; FERRAZ-DE-SOUZA, BrunoContext: The genetic bases of osteoporosis (OP), a disorder with high heritability, are poorly understood at an individual level. Cases of idiopathic or familial OP have long puzzled clinicians as to whether an actionable genetic cause could be identified. Objective: We performed a genetic analysis of 28 cases of idiopathic, severe, or familial osteoporosis using targeted massively parallel sequencing. Design: Targeted sequencing of 128 candidate genes was performed using Illumina NextSeq. Variants of interest were confirmed by Sanger sequencing or SNP array. Patients and Setting: Thirty-seven patients in an academic tertiary hospital participated (54% male; median age, 44 years; 86% with fractures), corresponding to 28 sporadic or familial cases. Main Outcome Measure: The identification of rare stop-gain, indel, splice site, copy-number, or nonsynonymous variants altering protein function. Results: Altogether, we identified 28 variants of interest, but only 3 were classified as pathogenic or likely pathogenic variants: COL1A2 p.(Arg708Gln), WNT1 p.(Gly169Asp), and IDUA p.(His82Gln). An association of variants in different genes was found in 21% of cases, including a young woman with severe OP bearing WNT1, PLS3, and NOTCH2 variants. Among genes of uncertain significance analyzed, a potential additional line of evidence has arisen for GWAS candidates GPR68 and NBR1, warranting further studies. Conclusions: While we hope that continuing efforts to identify genetic predisposition to OP will lead to improved and personalized care in the future, the likelihood of identifying actionable pathogenic variants in intriguing cases of idiopathic or familial osteoporosis is seemingly low.
conferenceObject High Prevalence of Nephrolithiasis and Hypercalciuria in Women with Osteogenesis Imperfecta(2018) SIMOES, Vivian Rf; FERNANDES, Adriana M.; ROCHA-BRAZ, Manuela Gm; MARTIN, Regina M.; FERRAZ-DE-SOUZA, Bruno