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Genetic bases of Syndromic Obesity and molecular mechanisms involved in its physiopathology

Grant number: 18/08486-3
Support Opportunities:Scholarships in Brazil - Doctorate
Effective date (Start): March 01, 2019
Effective date (End): December 31, 2022
Field of knowledge:Biological Sciences - Genetics - Human and Medical Genetics
Principal Investigator:Carla Rosenberg
Grantee:Laura Machado Lara Carvalho
Host Institution: Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated research grant:13/08028-1 - CEGH-CEL - Human Genome and Stem Cell Research Center, AP.CEPID


Syndromic Obesity is a rare pathology of great phenotypic variability, which is defined by the association of obesity with one or more of the following characteristics: neuropsychomotor developmental delay, dysmorphic features and/or congenital malformations. Unfortunately, most cases of Syndromic Obesity do not have their genetic origin elucidated. Objectives: Identify candidate genetic variants and elucidate the involved pathophysiological mechanisms. Methods: We will perform exome sequencing by NGS (Next Generation Sequencing) of 30 patients and their parents, previously excluded cases of genomic unbalance or chromosomal alterations (detected by CGH-array). For functional validation, zebrafish will be submitted to genetic editing by the CRISPR technique, in order to present the genetic variants identified as candidates in the patient's exome analysis. Subsequently, these animals will be compared to wild type animals by transcriptomic (RNAseq) and morphological analysis (histology and body measurements). Finally, we intend to infer the pathological mechanisms triggered by the variants studied considering the comparative analyzes between animals carrying the variants and controls. Future perspectives: The identification of candidate genes and pathophysiological mechanisms will improve our knowledge of the mechanisms involved in Syndromic Obesity, and will reflect in more preciseclinical diagnosis and genetic counseling of the patients. In addition, the understanding of pathophysiology may be the basis for new studies involving therapeutic proposals, which could improve the quality of life of patients with this pathology or some of those symptoms. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
CARVALHO, L. M. L.; DA COSTA, S. S.; CAMPAGNARI, F.; KAUFMAN, A.; BERTOLA, D. R.; DA SILVA, I. T.; KREPISCHI, V, A. C.; KOIFFMANN, C. P.; ROSENBERG, C.. Two novel pathogenic variants in MED13L: one familial and one isolated case. JOURNAL OF INTELLECTUAL DISABILITY RESEARCH, v. 65, n. 12, . (18/08486-3, 13/08028-1, 12/50981-5)
CARVALHO, LAURA M. L.; D'ANGELO, CARLA S.; MUSTACCHI, ZAN; DA SILVA, ISRAEL T.; KREPISCHI, ANA CRISTINA V.; KOIFFMANN, CELIA P.; ROSENBERG, CARLA. A novel MYT1L mutation in a boy with syndromic obesity: Case report and literature review. OBESITY RESEARCH & CLINICAL PRACTICE, v. 15, n. 2, p. 124-132, . (13/08028-1, 18/08486-3)
Academic Publications
(References retrieved automatically from State of São Paulo Research Institutions)
CARVALHO, Laura Machado Lara. Genetic investigation of syndromic obesity and development of biological models to study the Xia-Gibbs syndrome. 2023. Doctoral Thesis - Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) São Paulo.

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