LIM/25 - Laboratório de Endocrinologia Celular e Molecular

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https://observatorio.fm.usp.br/handle/OPI/3694
O Laboratório de Endocrinologia Celular e Molecular é ligado ao Departamento de Clínica Médica da Faculdade de Medicina da Universidade de São Paulo (FMUSP).

Linhas de pesquisa: neoplasia endócrina múltipla tipo II; tumorigênese endócrina; diabetes mellitus; genes de candidatos a obesidade e obesidade infantil; biologia molecular da tireoide; genética do hipotireoidismo congênito e do câncer de tireoide; terapia gênica para câncer de tireoide; avaliação da excreção urinária da população.

Site oficial: http://limhc.fm.usp.br/portal/lim25-laboratorio-de-endocrinologia-celular-e-molecular/

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article 2 Citação(ões) na Scopus
Variants in 46,XY DSD-Related Genes in Syndromic and Non-Syndromic Small for Gestational Age Children with Hypospadias
(2022) BRAGA, B. L.; GOMES, N. L.; NISHI, M. Y.; FREIRE, B. L.; BATISTA, R. L.; FARIA JUNIOR, J. A. D.; FUNARI, M. F. A.; BENEDETTI, A. F. F.; NARCIZO, A. De Moraes; CARDOSO, L. Cavalca; LERARIO, A. M.; GUERRA-JUNIOR, G.; COSTA, E. M. F.; DOMENICE, S.; JORGE, A. A. L.; MENDONCA, B. B.
Hypospadias is a common congenital disorder of male genital formation. Children born small for gestational age (SGA) present a high frequency of hypospadias of undetermined etiology. No previous study investigated the molecular etiology of hypospadias in boys born SGA using massively parallel sequencing. Our objective is to report the genetic findings of a cohort of patients born SGA with medium or proximal hypospadias. We identified 46 individuals with this phenotype from a large cohort of 46,XY DSD patients, including 5 individuals with syndromic features. DNA samples from subjects were studied by either whole exome sequencing or target gene panel approach. Three of the syndromic patients have 5 main clinical features of Silver-Russell syndrome (SRS) and were first studied by MLPA. Among the syndromic patients, loss of DNA methylation at the imprinting control region H19/IGF2 was identified in 2 individuals with SRS clinical diagnosis. Two novel pathogenic variants in compound heterozygous state were identified in the CUL7 gene establishing the diagnosis of 3M syndrome in one patient, and a novel homozygous variant in TRIM37 was identified in another boy with Mulibrey nanism phenotype. Among the non-syndromic subjects, 7 rare heterozygous variants were identified in 6 DSD-related genes. However, none of the variants found can explain the phenotype by themselves. In conclusion, a genetic defect that clarifies the etiology of hypospadias was not found in most of the non-syndromic SGA children, supporting the hypothesis that multifactorial causes, new genes, and/or unidentified epigenetic defects may have an influence in this condition.
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RESPONSE TO RHGH THERAPY IN SHORT CHILDREN BORN AT VERY LOW BIRTH WEIGHT
(2023) MALAQUIAS, A. C.; HOMMA, T.; DANTAS, M. C. B.; FREIRE, B. L.; ALBUQUE, E. V. A.; ARNHOLD, I. J. P.; VASQUES, G. A.; JORGE, A. A. L.
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A systematic review of core outcomes reported in clinical trials of growth hormone therapy in children with growth hormone deficiency
(2023) TSERETOPOULOU, Xanthippi; LUCAS-HERALD, Angela; CHEN, Jiajia; BACHEGA, Tania; CHARMANDARI, Evangelia; CHOI, Jin-Ho; DOU, Xinyu; GONG, Chunxiu; HAMZA, Rasha; HARVEY, Jamie; HOFFMAN, Andrew R.; HORIKAWA, Reiko; JOHANNSSON, Gudmundur; JORGE, Alexander; MILLER, Bradley S.; ROEHRICH, Sebastian; SAVENDAHL, Lars; VITALI, Diana; WAJNRAJCH, Michael; CHEN, Suet Ching; AHMED, Syed Faisal
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Genetic evaluation in children with self-limited pubertal delay discloses new candidate genes
(2023) REZENDE, Raissa; SCHAFER, Evan; KAISINGER, Lena; HE, Wen; ANDRADE, Nathalia; DANTAS, Naiara; CELLIN, Laurana; QUEDAS, Elisangela; PERRY, John; HOWARD, Sasha; LATRONICO, Ana Claudia; CHAN, Yee-Ming; JORGE, Alexander
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Outcomes in growth hormone (GH)-treated Noonan syndrome (NS) children: impact of PTPN11 mutation status
(2023) JORGE, Alexander; PIETROPOLI, Alberto; KELEPOURIS, Nicky; HORIKAWA, Reiko
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Clinical predictors of good/poor response to growth hormone treatment (GHT) in children with idiopathic short stature (ISS)
(2023) DAUBER, Andrew; PHILLIP, Moshe; FERRAN, Jean-Marc; KELEPOURIS, Nicky; NEDJATIAN, Navid; OLSEN, Anne Helene; JORGE, Alexander
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Retrospective Analysis of Individuals with Differences in Sex Development (DSD) in a Brazilian Single-Center Study Across the Lifespan
(2023) BATISTA, Rafael; GOMES, Nathalia; BACHEGA, Tania; MADUREIRA, Guiomar; MIRANDA, Mirela; DALLAGO, Renata; TERESA, Maria; LOUSADA, Ferrari Lia; CRAVEIRO, Flora; BATATINHA, Julio; SCALCO, Renata; JORGE, Alexander; COSTA, Elaine; SIRCILI, Maria Helena; DENES, Francisco; INACIO, Marlene; NISHI, Mirian; DOMENICE, Sorahia; MENDONCA, Berenice
article 21 Citação(ões) na Scopus
International Consensus Guideline on Small for Gestational Age: Etiology and Management From Infancy to Early Adulthood
(2023) HOKKEN-KOELEGA, Anita C. S.; STEEN, Manouk van der; BOGUSZEWSKI, Margaret C. S.; CIANFARANI, Stefano; DAHLGREN, Jovanna; HORIKAWA, Reiko; MERICQ, Veronica; RAPAPORT, Robert; ALHERBISH, Abdullah; BRASLAVSKY, Debora; CHARMANDARI, Evangelia; CHERNAUSEK, Steven D.; CUTFIELD, Wayne S.; DAUBER, Andrew; DEEB, Asma; GOEDEGEBUURE, Wesley J.; HOFMAN, Paul L.; ISGANATIS, Elvira; JORGE, Alexander A.; KANAKA-GANTENBEIN, Christina; KASHIMADA, Kenichi; KHADILKAR, Vaman; LUO, Xiao-Ping; MATHAI, Sarah; NAKANO, Yuya; YAU, Mabel
This International Consensus Guideline was developed by experts in the field of small for gestational age (SGA) of 10 pediatric endocrine societies worldwide. A consensus meeting was held and 1300 articles formed the basis for discussions. All experts voted about the strengths of the recommendations. The guideline gives new and clinically relevant insights into the etiology of short stature after SGA birth, including novel knowledge about (epi)genetic causes. Further, it presents long-term consequences of SGA birth and also reviews new treatment options, including treatment with gonadotropin-releasing hormone agonist (GnRHa) in addition to growth hormone (GH) treatment, as well as the metabolic and cardiovascular health of young adults born SGA after cessation of childhood GH treatment in comparison with appropriate control groups. To diagnose SGA, accurate anthropometry and use of national growth charts are recommended. Follow-up in early life is warranted and neurodevelopment evaluation in those at risk. Excessive postnatal weight gain should be avoided, as this is associated with an unfavorable cardiometabolic health profile in adulthood. Children born SGA with persistent short stature < -2.5 SDS at age 2 years or < -2 SDS at 3 to 4 years of age, should be referred for diagnostic workup. In case of dysmorphic features, major malformations, microcephaly, developmental delay, intellectual disability, and/or signs of skeletal dysplasia, genetic testing should be considered. Treatment with 0.033 to 0.067 mg GH/kg/day is recommended in case of persistent short stature at age of 3 to 4 years. Adding GnRHa treatment could be considered when short adult height is expected at pubertal onset. All young adults born SGA require counseling to adopt a healthy lifestyle.
article 0 Citação(ões) na Scopus
Identification of a second genetic alteration in patients with SHOX deficiency individuals: a potential explanation for phenotype variability
(2023) DANTAS, Naiara C. B.; FUNARI, Mariana F. A.; LERARIO, Antonio M.; ANDRADE, Nathalia L. M.; REZENDE, Raissa C.; CELLIN, Laurana P.; ALVES, Cresio; CRISOSTOMO, Lindiane G.; ARNHOLD, Ivo J. P.; MENDONCA, Berenice; SCALCO, Renata C.; JORGE, Alexander A. L.
Objective Our study aimed to assess the impact of genetic modifiers on the significant variation in phenotype that is observed in individuals with SHOX deficiency, which is the most prevalent monogenic cause of short stature.Design and methods We performed a genetic analysis in 98 individuals from 48 families with SHOX deficiency with a target panel designed to capture the entire SHOX genomic region and 114 other genes that modulate growth and/or SHOX action. We prioritized rare potentially deleterious variants.Results We did not identify potential deleterious variants in the promoter or intronic regions of the SHOX genomic locus. In contrast, we found eight heterozygous variants in 11 individuals from nine families in genes with a potential role as genetic modifiers. In addition to a previously described likely pathogenic (LP) variant in CYP26C1 observed in two families, we identified LP variants in PTHLH and ACAN, and variants of uncertain significance in NPR2, RUNX2, and TP53 in more affected individuals from families with SHOX deficiency. Families with a SHOX alteration restricted to the regulatory region had a higher prevalence of a second likely pathogenic variant (27%) than families with an alteration compromising the SHOX coding region (2.9%, P = .04).Conclusion In conclusion, variants in genes related to the growth plate have a potential role as genetic modifiers of the phenotype in individuals with SHOX deficiency. In individuals with SHOX alterations restricted to the regulatory region, a second alteration could be critical to determine the penetrance and expression of the phenotype.
article 1 Citação(ões) na Scopus
The Effect of Gene Editing by CRISPR-Cas9 of miR-21 and the Indirect Target MMP9 in Metastatic Prostate Cancer
(2023) CAMARGO, Juliana A.; VIANA, Nayara I.; PIMENTA, Ruan; GUIMARAES, Vanessa R.; SANTOS, Gabriel A. dos; CANDIDO, Patricia; GHAZARIAN, Vitoria; ROMAO, Poliana; SILVA, Iran A.; BIRBRAIR, Alexander; SROUGI, Miguel; NAHAS, William C.; LEITE, Katia R.; TRARBACH, Ericka B.; REIS, Sabrina T.
Prostate cancer (PCa) has a high prevalence and represents an important health problem, with an increased risk of metastasis. With the advance of CRISPR-Cas9 genome editing, new possibilities have been created for investigating PCa. The technique is effective in knockout oncogenes, reducing tumor resistance. MMP9 and miR-21 target genes are associated with PCa progression; therefore, we evaluated the MMP-9 and miR-21 targets in PCa using the CRISPR-Cas9 system. Single guide RNAs (sgRNAs) of MMP9 and miR-21 sequences were inserted into a PX-330 plasmid, and transfected in DU145 and PC-3 PCa cell lines. MMP9 and RECK expression was assessed by qPCR, WB, and IF. The miR-21 targets, integrins, BAX and mTOR, were evaluated by qPCR. Flow cytometry was performed with Annexin5, 7-AAD and Ki67 markers. Invasion assays were performed with Matrigel. The miR-21 CRISPR-Cas9-edited cells upregulated RECK, MARCKS, BTG2, and PDCD4. CDH1, ITGB3 and ITGB1 were increased in MMP9 and miR-21 CRISPR-Cas9-edited cells. Increased BAX and decreased mTOR were observed in MMP9 and miR-21 CRISPR-Cas9-edited cells. Reduced cell proliferation, increased apoptosis and low invasion in MMP9 and miR-21 edited cells was observed, compared to Scramble. CRISPR-Cas9-edited cells of miR-21 and MMP9 attenuate cell proliferation, invasion and stimulate apoptosis, impeding PCa evolution.