DEBORA ROMEO BERTOLA
Projetos de Pesquisa
Unidades Organizacionais
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina - Médico
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
BIO, IB
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
12 resultados
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- A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: Description of two unrelated cases from Brazil(2011) JESUS, Adriana A.; OSMAN, Mazen; SILVA, Clovis A.; KIM, Peter W.; Tuyet-Hang Pham; GADINA, Massimo; YANG, Barbara; BERTOLA, Debora R.; CARNEIRO-SAMPAIO, Magda; FERGUSON, Polly J.; RENSHAW, Blair R.; SCHOOLEY, Ken; BROWN, Michael; AL-DOSARI, Asma; AL-ALAMI, Jamil; SIMS, John E.; GOLDBACH-MANSKY, Raphaela; EL-SHANTI, HatemObjective Monogenic autoinflammatory diseases are disorders of Mendelian inheritance that are characterized by mutations in genes that regulate innate immunity and whose typical features are systemic inflammation without high-titer autoantibodies or antigen-specific T cells. Skin and bone inflammation in the newborn period have been described in 3 of these autoinflammatory disorders: neonatal-onset multisystem inflammatory disease, Majeed syndrome, and deficiency of interleukin-1 (IL-1) receptor antagonist (DIRA) syndrome. This study was undertaken to present the characteristics of the DIRA syndrome in 2 cases from Brazil, and describe a novel mutation in IL1RN. Methods. Two unrelated Brazilian patients were evaluated for the clinical signs and symptoms of these 3 disorders, and peripheral blood samples were assessed for mutations in NLRP3, LPIN2, and IL1RN by DNA resequencing analysis. A mutation in IL1RN that encodes a mutant protein was identified, and the expression and function of this mutant protein were compared to those of the wild-type protein. Results. Both patients presented with pustular dermatitis resembling generalized pustular psoriasis, recurrent multifocal aseptic osteomyelitis, and elevation in the levels of acute-phase reactants, all of which are features most consistent with the DIRA syndrome. Chronic lung disease was observed in 1 of the patients, and jugular venous thrombosis was observed in the other patient. Both patients showed a partial response to corticosteroid therapy, and 1 patient experienced an initial improvement of dermatitis with the use of acitretin. Both patients were homozygous for a novel 15-bp (in-frame) deletion on the IL1RN gene. The mutated protein expressed in vitro had no affinity with the IL-1 receptor, and stimulation of the patients' cells with recombinant human IL-1 alpha or IL-1 alpha led to oversecretion of proinflammatory cytokines, similar to the findings obtained in previously reported patients. Conclusion. The presence of the same homozygous novel mutation in IL1RN in 2 unrelated Brazilian patients suggests that this genetic variant may be a founder mutation that has been introduced in the Brazilian population.
- Nosology of genetic skeletal disorders: 2023 revision(2023) UNGER, Sheila; FERREIRA, Carlos R. R.; MORTIER, Geert R. R.; ALI, Houda; BERTOLA, Debora R.; CALDER, Alistair; COHN, Daniel H. H.; CORMIER-DAIRE, Valerie; GIRISHA, Katta M. M.; HALL, Christine; KRAKOW, Deborah; MAKITIE, Outi; MUNDLOS, Stefan; NISHIMURA, Gen; ROBERTSON, Stephen P. P.; SAVARIRAYAN, Ravi; SILLENCE, David; SIMON, Marleen; SUTTON, V. Reid; WARMAN, Matthew L. L.; SUPERTI-FURGA, AndreaThe ""Nosology of genetic skeletal disorders"" has undergone its 11th revision and now contains 771 entries associated with 552 genes reflecting advances in molecular delineation of new disorders thanks to advances in DNA sequencing technology. The most significant change as compared to previous versions is the adoption of the dyadic naming system, systematically associating a phenotypic entity with the gene it arises from. We consider this a significant step forward as dyadic naming is more informative and less prone to errors than the traditional use of list numberings and eponyms. Despite the adoption of dyadic naming, efforts have been made to maintain strong ties to the MIM catalog and its historical data. As with the previous versions, the list of disorders and genes in the Nosology may be useful in considering the differential diagnosis in the clinic, directing bioinformatic analysis of next-generation sequencing results, and providing a basis for novel advances in biology and medicine.
- Rothmund-Thomson syndrome, a disorder far from solved(2023) MARTINS, Davi Jardim; LAZZARO FILHO, Ricardo Di; BERTOLA, Debora Romeo; HOCH, Nicolas CarlosRothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder characterized by a range of clinical symptoms, including poikiloderma, juvenile cataracts, short stature, sparse hair, eyebrows/eyelashes, nail dysplasia, and skeletal abnormalities. While classically associated with mutations in the RECQL4 gene, which encodes a DNA helicase involved in DNA replication and repair, three additional genes have been recently identified in RTS: ANAPC1, encoding a subunit of the APC/C complex; DNA2, which encodes a nuclease/helicase involved in DNA repair; and CRIPT, encoding a poorly characterized protein implicated in excitatory synapse formation and splicing. Here, we review the clinical spectrum of RTS patients, analyze the genetic basis of the disease, and discuss molecular functions of the affected genes, drawing some novel genotype-phenotype correlations and proposing avenues for future studies into this enigmatic disorder.
- POLR1A variants underlie phenotypic heterogeneity in craniofacial, neural, and cardiac anomalies(2023) SMALLWOOD, Kelly; WATT, Kristin E. N.; IDE, Satoru; BALTRUNAITE, Kristina; BRUNSWICK, Chad; INSKEEP, Katherine; CAPANNARI, Corrine; ADAM, Margaret P.; BEGTRUP, Amber; BERTOLA, Debora R.; DEMMER, Laurie; DEMO, Erin; DEVINSKY, Orrin; GALLAGHER, Emily R.; SACOTO, Maria J. Guillen; JECH, Robert; KEREN, Boris; KUSSMANN, Jennifer; LADDA, Roger; LANSDON, Lisa A.; LUNKE, Sebastian; MARDY, Anne; MCWALTERS, Kirsty; PERSON, Richard; RAITI, Laura; SAITOH, Noriko; SAUNDERS, Carol J.; SCHNUR, Rhonda; SKORVANEK, Matej; SELL, Susan L.; SLAVOTINEK, Anne; SULLIVAN, Bonnie R.; STARK, Zornitza; SYMONDS, Joseph D.; WENGER, Tara; WEBER, Sacha; WHALEN, Sandra; WHITE, Susan M.; WINKELMANN, Juliane; ZECH, Michael; ZEIDLER, Shimriet; MAESHIMA, Kazuhiro; STOTTMANN, Rolf W.; TRAINOR, Paul A.; WEAVER, K. NicoleHeterozygous pathogenic variants in POLR1A, which encodes the largest subunit of RNA Polymerase I, were previously identified as the cause of acrofacial dysostosis, Cincinnati-type. The predominant phenotypes observed in the cohort of 3 individuals were craniofacial anomalies reminiscent of Treacher Collins syndrome. We subsequently identified 17 additional individuals with 12 unique heterozygous variants in POLR1A and observed numerous additional phenotypes including neurodevelopmental abnormalities and structural cardiac defects, in combination with highly prevalent craniofacial anomalies and variable limb defects. To understand the pathogenesis of this pleiotropy, we modeled an allelic series of POLR1A variants in vitro and in vivo. In vitro assessments demonstrate variable effects of indi-vidual pathogenic variants on ribosomal RNA synthesis and nucleolar morphology, which supports the possibility of variant-specific phenotypic effects in affected individuals. To further explore variant-specific effects in vivo, we used CRISPR-Cas9 gene editing to reca-pitulate two human variants in mice. Additionally, spatiotemporal requirements for Polr1a in developmental lineages contributing to congenital anomalies in affected individuals were examined via conditional mutagenesis in neural crest cells (face and heart), the second heart field (cardiac outflow tract and right ventricle), and forebrain precursors in mice. Consistent with its ubiquitous role in the essential function of ribosome biogenesis, we observed that loss of Polr1a in any of these lineages causes cell-autonomous apoptosis resulting in embryonic malformations. Altogether, our work greatly expands the phenotype of human POLR1A-related disorders and demonstrates variant-specific effects that provide insights into the underlying pathogenesis of ribosomopathies.
- Childhood Hypophosphatasia Associated with a Novel Biallelic ALPL Variant at the TNSALP Dimer Interface(2023) MARTINS, Luciane; LESSA, Luis Gustavo F.; ALI, Taccyanna M. M.; LAZAR, Monize; KIM, Chong A. A.; KANTOVITZ, Kamila R. R.; SANTAMARIA, Mauro P. P.; ARAUJO, Cassia F.; RAMOS, Carolina J. J.; FOSTER, Brian L. L.; FRANCO, Jose Francisco S.; BERTOLA, Debora; JR, Francisco H. H. NocitiThe goal of this study was to perform a clinical and molecular investigation in an eight-year-old female child diagnosed with hypophosphatasia (HPP). The proband and her family were evaluated by medical and dental histories, biochemical analyses, radiographic imaging, and genetic analysis of the tissue-nonspecific alkaline phosphatase (ALPL) gene. A bioinformatic analysis was performed to predict the structural and functional impact of the point mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) molecule and to define their potential contribution to the phenotype. We identified a novel combination of heterozygous ALPL missense variants in the proband, p.Ala33Val and p.Asn47His, compatible with an autosomal recessive mode of inheritance and resulting in skeletal and dental phenotypes. Computational modeling showed that the affected Asn47 residue is located in the coil structure close to the N-terminal alpha-helix, whereas the affected Ala33 residue is localized in the N-terminal alpha-helix. Both affected residues are located close to the homodimer interface, suggesting they may impair TNSALP dimer formation and stability. Clinical and biochemical follow-up revealed improvements after six years of ERT. Reporting this novel combination of ALPL variants in childhood HPP provides new insights into genotype-phenotype associations for HPP and specific sites within the TNSALP molecule potentially related to a childhood-onset HPP and skeletal and dental manifestations. Beneficial effects of ERT are implicated in skeletal and dental tissues.
- A rare case of hepatoblastoma in a syndromic child with a de novo germline JAG1 mutation(2023) DANGONI, Gustavo Dib; TEIXEIRA, Anne Caroline Barbosa; AGUIAR, Talita Ferreira; SUGAYAMA, Sofia Mizuho Miura; FILHO, Vicente Odone; BERTOLA, Debora Romeo; KREPISCHI, Ana Cristina Victorino
- Skewed X-chromosome Inactivation in Women with Idiopathic Intellectual Disability is Indicative of Pathogenic Variants(2023) CHAVES, Luiza D.; CARVALHO, Laura M. L.; TOLEZANO, Giovanna C.; PIRES, Sara F.; COSTA, Silvia S.; SCLIAR, Marilia de O.; GIULIANI, Liane de R.; BERTOLA, Debora R.; SANTOS-REBOUCAS, Cintia B.; SEO, Go Hun; OTTO, Paulo A.; ROSENBERG, Carla; VIANNA-MORGANTE, Angela M.; KREPISCHI, Ana C. V.Intellectual disability (ID) is an early onset impairment in cognitive functioning and adaptive behavior, affecting approximately 1% of the population worldwide. Extreme skewing of X-chromosome inactivation (XCI) can be associated with ID phenotypes caused by pathogenic variants in the X chromosome. We analyzed the XCI pattern in blood samples of 194 women with idiopathic ID, using the androgen receptor gene (AR) methylation assay. Among the 136 patients who were informative, 11 (8%) presented with extreme or total XCI skewing (>= 90%), which was significantly higher than expected by chance. Whole-exome data obtained from these 11 patients revealed the presence of dominant pathogenic variants in eight of them, all sporadic cases, resulting in a molecular diagnostic rate of 73% (8/11 patients). All variants were mapped to ID-related genes with dominant phenotypes: four variants in the X-linked genes DDX3X (an XCI escape gene; two cases), WDR45, and PDHA1, and four variants in the autosomal genes KCNB1, CTNNB1, YY1, and ANKRD11. Three of the autosomal genes had no obvious correlation with the observed XCI skewing. However, YY1 is a known transcriptional repressor that acts in the binding of the XIST long noncoding RNA on the inactive X chromosome, providing a mechanistic link between the pathogenic variant and the detected skewed XCI in the carrier. These data confirm that extreme XCI skewing in females with ID is highly indicative of causative X-linked pathogenic variants, and point to the possibility of identifying causative variants in autosomal genes with a XCI role.
- Delayed Puberty Phenotype Observed in Noonan Syndrome Is More Pronounced in Girls than Boys(2022) REZENDE, Raissa C.; NORONHA, Renata Maria; KESELMAN, Ana; QUEDAS, Elisangela P. S.; DANTAS, Naiara C. B.; ANDRADE, Nathalia L. M.; BERTOLA, Debora R.; MALAQUIAS, Alexsandra C.; JORGE, Alexander A. L.Introduction: Pubertal delay is described as one of the clinical features in Noonan syndrome (NS) and it may be one of the factors causing short adult height in those patients. The present study aimed at characterizing pubertal development in NS and identifying pubertal delay predictors. Methods: We analyzed 133 individuals with a molecular diagnosis of NS and clinical puberty evaluation. We characterized delayed puberty as pubertal onset after 12 years in girls and 13.5 years in boys, according to parameters of the Brazilian population. To investigate its predictors, we correlated the age at onset of puberty with several characteristics and genotype in a multilevel regression model. For comprehending pubertal development in NS, we assessed age and anthropometric measures at each Tanner stage and adult age. Results: The mean age at puberty onset for girls was 11.9 +/- 1.9 years and for boys, 12.5 +/- 1.7 years, significantly later than the Brazilian population (p = 0.025; p < 0.001). Girls (49.1%) presented delayed puberty more frequently than boys (27.9%, p = 0.031). Body mass index standard deviation scores (SDS) and insulin growth factor 1 SDS at puberty onset significantly predicted later puberty entry. Height gain from the onset of puberty to adult height was lower in children with pubertal delay. Conclusion: Pubertal delay is characteristically found in children with NS, more frequently in females. The low weight of patients with NS could modulate the age of puberty, just as the increase in overweight/obesity in the general population has shown an effect on reducing the age of onset of puberty.
- Imagawa-Matsumoto syndrome: SUZ12-related overgrowth disorder(2023) IMAGAWA, Eri; SEYAMA, Rie; AOI, Hiromi; UCHIYAMA, Yuri; MARCARINI, Bruno Guimaraes; FURQUIM, Isabel; HONJO, Rachel Sayuri; BERTOLA, Debora Romeo; KIM, Chong Ae; MATSUMOTO, NaomichiThe SUZ12 gene encodes a subunit of polycomb repressive complex 2 (PRC2) that is essential for development by silencing the expression of multiple genes. Germline heterozygous variants in SUZ12 have been found in Imagawa-Matsumoto syndrome (IMMAS) characterized by overgrowth and multiple dysmorphic features. Similarly, both EZH2 and EED also encode a subunit of PRC2 each and their pathogenic variants cause Weaver syndrome and Cohen-Gibson syndrome, respectively. Clinical manifestations of these syndromes significantly overlap, although their different prevalence rates have recently been noted: generalized overgrowth, intellectual disability, scoliosis, and excessive loose skin appear to be less prevalent in IMMAS than in the other two syndromes. We could not determine any apparent genotype-phenotype correlation in IMMAS. The phenotype of neurofibromatosis type 1 arising from NF1 deletion was also shown to be modified by the deletion of SUZ12, 560 kb away. This review deepens our understanding of the clinical and genetic characteristics of IMMAS together with other overgrowth syndromes related to PRC2. We also report on a novel IMMAS patient carrying a splicing variant (c.1023+1G>C) in SUZ12. This patient had a milder phenotype than other previously reported IMMAS cases, with no macrocephaly or overgrowth phenotypes, highlighting the clinical variation in IMMAS.
- Biallelic variants in DNA2 cause poikiloderma with congenital cataracts and severe growth failure reminiscent of Rothmund-Thomson syndrome(2023) LAZZARO FILHO, Ricardo Di; YAMAMOTO, Guilherme Lopes; SILVA, Tiago J.; ROCHA, Leticia A.; LINNENKAMP, Bianca D. W.; CASTRO, Matheus Augusto Araujo; BARTHOLDI, Deborah; SCHALLER, Andre; LEEB, Tosso; KELMANN, Samantha; UTAGAWA, Claudia Y.; STEINER, Carlos E.; STEINMETZ, Leandra; HONJO, Rachel Sayuri; KIM, Chong Ae; WANG, Lisa; ABOURJAILI-BILODEAU, Raphael; CAMPEAU, Philippe; WARMAN, Matthew; PASSOS-BUENO, Maria Rita; HOCH, Nicolas C.; BERTOLA, Debora RomeoRothmund-Thomson syndrome (RTS) is a rare, heterogeneous autosomal recessive genodermatosis, with poikiloderma as its hallmark. It is classified into two types: type I, with biallelic variants in ANAPC1 and juvenile cataracts, and type II, with biallelic variants in RECQL4, increased cancer risk and no cataracts. We report on six Brazilian probands and two siblings of Swiss/Portuguese ancestry presenting with severe short stature, widespread poikiloderma and congenital ocular anomalies. Genomic and functional analysis revealed compound heterozygosis for a deep intronic splicing variant in trans with loss of function variants in DNA2, with reduction of the protein levels and impaired DNA double-strand break repair. The intronic variant is shared by all patients, as well as the Portuguese father of the European siblings, indicating a probable founder effect. Biallelic variants in DNA2 were previously associated with microcephalic osteodysplastic primordial dwarfism. Although the individuals reported here present a similar growth pattern, the presence of poikiloderma and ocular anomalies is unique. Thus, we have broadened the phenotypical spectrum of DNA2 mutations, incorporating clinical characteristics of RTS. Although a clear genotype-phenotype correlation cannot be definitively established at this moment, we speculate that the residual activity of the splicing variant allele could be responsible for the distinct manifestations of DNA2-related syndromes.