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
20 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 20
- Unexpected role of SIX1 variants in craniosynostosis: expanding the phenotype of SIX1-related disorders(2022) CALPENA, Eduardo; WURMSER, Maud; MCGOWAN, Simon J.; ATIQUE, Rodrigo; BERTOLA, Debora R.; CUNNINGHAM, Michael L.; GUSTAFSON, Jonas A.; JOHNSON, David; V, Jenny E. Morton; PASSOS-BUENO, Maria Rita; TIMBERLAKE, Andrew T.; LIFTON, Richard P.; WALL, Steven A.; TWIGG, Stephen R. F.; MAIRE, Pascal; WILKIE, Andrew O. M.Background Pathogenic heterozygous SIX1 variants (predominantly missense) occur in branchio-otic syndrome (BOS), but an association with craniosynostosis has not been reported. Methods We investigated probands with craniosynostosis of unknown cause using whole exome/genome (n=628) or RNA (n=386) sequencing, and performed targeted resequencing of SIX1 in 615 additional patients. Expression of SIX1 protein in embryonic cranial sutures was examined in the Six1 ( nLacZ/+ ) reporter mouse. Results From 1629 unrelated cases with craniosynostosis we identified seven different SIX1 variants (three missense, including two de novo mutations, and four nonsense, one of which was also present in an affected twin). Compared with population data, enrichment of SIX1 loss-of-function variants was highly significant (p=0.00003). All individuals with craniosynostosis had sagittal suture fusion; additionally four had bilambdoid synostosis. Associated BOS features were often attenuated; some carrier relatives appeared non-penetrant. SIX1 is expressed in a layer basal to the calvaria, likely corresponding to the dura mater, and in the mid-sagittal mesenchyme. Conclusion Craniosynostosis is associated with heterozygous SIX1 variants, with possible enrichment of loss-of-function variants compared with classical BOS. We recommend screening of SIX1 in craniosynostosis, particularly when sagittal +/- lambdoid synostosis and/or any BOS phenotypes are present. These findings highlight the role of SIX1 in cranial suture homeostasis.
- 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.
- Serpentine fibula polycystic kidney syndrome is part of the phenotypic spectrum of Hajdu-Cheney syndrome(2012) GRAY, Mary J.; KIM, Chong Ae; BERTOLA, Debora Romeo; ARANTES, Paula Ricci; STEWART, Helen; SIMPSON, Michael A.; IRVING, Melita D.; ROBERTSON, Stephen P.Serpentine fibula polycystic kidney syndrome (SFPKS; MIM600330) is a rare skeletal dysplasia that has polycystic kidneys and dysmorphic facies as additional defining phenotypic components. The nosological classification of this disease has been debated as the condition shares features common to other skeletal dysplasias such as Melnick Needles syndrome (MNS; MIM309350) and Hajdu-Cheney Syndrome (HCS; MIM102500). Here, two previously reported cases of SFPKS are presented with emphasis on their phenotypic evolution. With the recent discovery that HCS is caused by mutations in NOTCH2, DNA from the both cases was examined and both were found to have truncating mutations in exon 34 of NOTCH2. The phenotypic evolution of SFPKS and this molecular analysis strongly suggest that SFPKS is part of the phenotypic spectrum of HCS and should no longer be classified as a distinct disease entity. European Journal of Human Genetics (2012) 20, 122-124; doi:10.1038/ejhg.2011.125; published online 29 June 2011
conferenceObject Severe Osteogenesis imperfecta with oligodontia: think of MESD(2020) MOOSA, S.; YAMAMOTO, G. L.; GARBES, L.; KEUPP, K.; BELEZA-MEIRELES, A.; MORENO, C. A.; VALADARES, E. R.; SOUSA, S. B. de; MAIA, S.; SARAIVA, J.; HONJO, R. S.; KIM, C. A.; MENEZES, H. Cabral de; LAUSCH, E.; LORINI, P. V.; LAMOUNIER JR., A.; CARNIERO, T. C. B.; GIUNTA, C.; ROHRBACH, M.; JANNER, M.; SEMLER, O.; BELEGGIA, F.; LI, Y.; YIGIT, G.; REINTJES, N.; ALTMULLER, J.; NURNBERG, P.; CAVALCANTI, D. P.; ZABEL, B.; WARMAN, M. L.; BERTOLA, D. R.; WOLLNIK, B.; NETZER, C.- Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta(2019) MOOSA, Shahida; YAMAMOTO, Guilherme L.; GARBES, Lutz; KEUPP, Katharina; BELEZA-MEIRELES, Ana; MORENO, Carolina Araujo; VALADARES, Eugenia Ribeiro; SOUSA, Sergio B. de; MAIA, Sofia; SARAIVA, Jorge; HONJO, Rachel S.; KIM, Chong Ae; MENEZES, Hamilton Cabral de; LAUSCH, Ekkehart; LORINI, Pablo Villavicencio; LAMOUNIER JR., Arsonval; CARNIERO, Tulio Canella Bezerra; GIUNTA, Cecilia; ROHRBACH, Marianne; JANNER, Marco; SEMLER, Oliver; BELEGGIA, Filippo; LI, Yun; YIGIT, Goekhan; REINTJES, Nadine; ALTMUELLER, Janine; NUERNBERG, Peter; CAVALCANTI, Denise P.; ZABEL, Bernhard; WARMAN, Matthew L.; BERTOLA, Debora R.; WOLLNIK, Bernd; NETZER, ChristianOsteogenesis imperfecta (OI) comprises a genetically heterogeneous group of skeletal fragility diseases. Here, we report on five independent families with a progressively deforming type of OI, in whom we identified four homozygous truncation or frameshift mutations in MESD. Affected individuals had recurrent fractures and at least one had oligodontia. MESD encodes an endoplasmic reticulum (ER) chaperone protein for the canonical Wingless-related integration site (WNT) signaling receptors LRP5 and LRP6. Because complete absence of MESD causes embryonic lethality in mice, we hypothesized that the OI-associated mutations are hypomorphic alleles since these mutations occur downstream of the chaperone activity domain but upstream of ER-retention domain. This would be consistent with the clinical phenotypes of skeletal fragility and oligodontia in persons deficient for LRP5 and LRP6, respectively. When we expressed wild-type (WT) and mutant MESD in HEK293T cells, we detected WT MESD in cell lysate but not in conditioned medium, whereas the converse was true for mutant MESD. We observed that both WT and mutant MESD retained the ability to chaperone LRP5. Thus, 01-associated MESD mutations produce hypomorphic alleles whose failure to remain within the ER significantly reduces but does not completely eliminate LRP5 and LRP6 trafficking. Since these individuals have no eye abnormalities (which occur in individuals completely lacking LRP5) and have neither limb nor brain patterning defects (both of which occur in mice completely lacking LRP6), we infer that bone mass accrual and dental patterning are more sensitive to reduced canonical WNT signaling than are other developmental processes. Biologic agents that can increase LRP5 and LRP6-mediated WNT signaling could benefit individuals with MESD-associated OI.
- Mutations in MAP3K7 that Alter the Activity of the TAK1 Signaling Complex Cause Frontometaphyseal Dysplasia(2016) WADE, Emma M.; DANIEL, Philip B.; JENKINS, Zandra A.; MCINERNEY-LEO, Aideen; LEO, Paul; MORGAN, Tim; ADDOR, Marie Claude; ADES, Lesley C.; BERTOLA, Debora; BOHRING, Axel; CARTER, Erin; CHO, Tae-Joon; DUBA, Hans-Christoph; FLETCHER, Elaine; KIM, Chong A.; KRAKOW, Deborah; MORAVA, Eva; NEUHANN, Teresa; SUPERTI-FURGA, Andrea; VEENSTRA-KNOL, Irma; WIECZOREK, Dagmar; WILSON, Louise C.; HENNEKAM, Raoul C. M.; SUTHERLAND-SMITH, Andrew J.; STROM, Tim M.; WILKIE, Andrew O. M.; BROWN, Matthew A.; DUNCAN, Emma L.; MARKIE, David M.; ROBERTSON, Stephen P.Frontometaphyseal dysplasia (FMD) is a progressive sclerosing skeletal dysplasia affecting the long bones and skull. The cause of FMD in some individuals is gain-of-function mutations in FLNA, although how these mutations result in a hyperostotic phenotype remains unknown. Approximately one half of individuals with FMD have no identified mutation in FLNA and are phenotypically very similar to individuals with FLNA mutations, except for an increased tendency to form keloid scars. Using whole-exome sequencing and targeted Sanger sequencing in 19 FMD-affected individuals with no identifiable FLNA mutation, we identified mutations in two genes-MAP3K7, encoding transforming growth factor beta (TGF-beta)-activated kinase (TAK1), and TAB2, encoding TAK1-associated binding protein 2 (TAB2). Four mutations were found in MAP3K7, including one highly recurrent (n = 15) de novo mutation (c.1454C>T [p.Pro485Leu]) proximal to the coiled-coil domain of TAK1 and three missense mutations affecting the kinase domain (c.208G>C[p.Glu70Gln], c.299T>A[p.Val100Glu], and c.502G>C [p.Gly168Arg]). Notably, the subjects with the latter three mutations had a milder FMD phenotype. An additional de novo mutation was found in TAB2 (c.1705G>A, p.Glu569Lys). The recurrent mutation does not destabilize TAK1, or impair its ability to homodimerize or bind TAB2, but it does increase TAK1 autophosphorylation and alter the activity of more than one signaling pathway regulated by the TAK1 kinase complex. These findings show that dysregulation of the TAK1 complex produces a close phenocopy of FMD caused by FLNA mutations. Furthermore, they suggest that the pathogenesis of some of the filaminopathies caused by FLNA mutations might be mediated by misregulation of signaling coordinated through the TAK1 signaling complex.
- Lipoid proteinosis: Rare case confirmed by ECM1 mutation detection(2014) ALMEIDA, Tatiana F.; SOARES, Diogo C.; QUAIO, Caio R.; HONJO, Rachel S.; BERTOLA, Debora R.; MCGRATH, John A.; KIM, Chong A.
- Genotype-Phenotype Correlation in NF1: Evidence for a More Severe Phenotype Associated with Missense Mutations Affecting NF1 Codons 844-848(2018) KOCZKOWSKA, Magdalena; CHEN, Yunjia; CALLENS, Tom; GOMES, Alicia; SHARP, Angela; JOHNSON, Sherrell; HSIAO, Meng-Chang; CHEN, Zhenbin; BALASUBRAMANIAN, Meena; BARNETT, Christopher P.; BECKER, Troy A.; BEN-SHACHAR, Shay; BERTOLA, Debora R.; BLAKELEY, Jaishri O.; BURKITT-WRIGHT, Emma M. M.; CALLAWAY, Alison; CRENSHAW, Melissa; CUNHA, Karin S.; CUNNINGHAM, Mitch; D'AGOSTINO, Maria D.; DAHAN, Karin; LUCA, Alessandro De; DESTREE, Anne; DHAMIJA, Radhika; EOLI, Marica; EVANS, D. Gareth R.; GALVIN-PARTON, Patricia; GEORGE-ABRAHAM, Jaya K.; GRIPP, Karen W.; GUEVARA-CAMPOS, Jose; HANCHARD, Neil A.; HERNANDEZ-CHICO, Concepcion; IMMKEN, LaDonna; JANSSENS, Sandra; JONES, Kristi J.; KEENA, Beth A.; KOCHHAR, Aaina; LIEBELT, Jan; MARTIR-NEGRON, Arelis; MAHONEY, Maurice J.; MAYSTADT, Isabelle; MCDOUGALL, Carey; MCENTAGART, Meriel; MENDELSOHN, Nancy; MILLER, David T.; MORTIER, Geert; MORTON, Jenny; PAPPAS, John; PLOTKIN, Scott R.; POND, Dinel; ROSENBAUM, Kenneth; RUBIN, Karol; RUSSELL, Laura; RUTLEDGE, Lane S.; SALETTI, Veronica; SCHONBERG, Rhonda; SCHREIBER, Allison; SEIDEL, Meredith; SIQVELAND, Elizabeth; STOCKTON, David W.; TREVISSON, Eva; ULLRICH, Nicole J.; UPADHYAYA, Meena; MINKELEN, Rick van; VERHELST, Helene; WALLACE, Margaret R.; YAP, Yoon-Sim; ZACKAI, Elaine; ZONANA, Jonathan; ZURCHER, Vickie; CLAES, Kathleen; MARTIN, Yolanda; KORF, Bruce R.; LEGIUS, Eric; MESSIAEN, Ludwine M.Neurofibromatosis type 1 (NF1), a common genetic disorder with a birth incidence of 1: 2,000-3,000, is characterized by a highly variable clinical presentation. To date, only two clinically relevant intragenic genotype-phenotype correlations have been reported for NF1 missense mutations affecting p. Arg1809 and a single amino acid deletion p.Met922del. Both variants predispose to a distinct mild NF1 phenotype with neither externally visible cutaneous/plexiform neurofibromas nor other tumors. Here, we report 162 individuals (129 unrelated probands and 33 affected relatives) heterozygous for a constitutional missense mutation affecting one of five neighboring NF1 codons-Leu844, Cys845, Ala846, Leu847, and Gly848-located in the cysteine-serine-rich domain (CSRD). Collectively, these recurrent missense mutations affect similar to 0.8% of unrelated NF1 mutation-positive probands in the University of Alabama at Birmingham (UAB) cohort. Major superficial plexiform neurofibromas and symptomatic spinal neurofibromas were more prevalent in these individuals compared with classic NF1-affected cohorts (both p < 0.0001). Nearly half of the individuals had symptomatic or asymptomatic optic pathway gliomas and/or skeletal abnormalities. Additionally, variants in this region seem to confer a high predisposition to develop malignancies compared with the general NF1-affected population (p = 0.0061). Our results demonstrate that these NF1 missense mutations, although located outside the GAP-related domain, may be an important risk factor for a severe presentation. A genotype-phenotype correlation at the NF1 region 844-848 exists and will be valuable in the management and genetic counseling of a significant number of individuals.
- Bi-allelic Variants in TONSL Cause SPONASTRIME Dysplasia and a Spectrum of Skeletal Dysplasia Phenotypes(2019) BURRAGE, Lindsay C.; REYNOLDS, John J.; BARATANG, Nissan Vida; PHILLIPS, Jennifer B.; WEGNER, Jeremy; MCFARQUHAR, Ashley; HIGGS, Martin R.; CHRISTIANSEN, Audrey E.; LANZA, Denise G.; SEAVITT, John R.; JAIN, Mahim; LI, Xiaohui; PARRY, David A.; RAMAN, Vandana; CHITAYAT, David; CHINN, Ivan K.; BERTUCH, Alison A.; KARAVITI, Lefkothea; SCHLESINGER, Alan E.; EARL, Dawn; BAMSHAD, Michael; SAVARIRAYAN, Ravi; DODDAPANENI, Harsha; MUZNY, Donna; JHANGIANI, Shalini N.; ENG, Christine M.; GIBBS, Richard A.; BI, Weimin; EMRICK, Lisa; ROSENFELD, Jill A.; POSTLETHWAIT, John; WESTERFIELD, Monte; DICKINSON, Mary E.; BEAUDET, Arthur L.; RANZA, Emmanuelle; HUBER, Celine; CORMIER-DAIRE, Valerie; SHEN, Wei; MAO, Rong; HEANEY, Jason D.; ORANGE, I. Jordan S.; BERTOLA, Debora; YAMAMOTO, Guilherme L.; BARATELA, Wagner Ar; BUTLER, Merlin G.; ALI, Asim; ADELI, Mehdi; COHN, Daniel H.; KRAKOW, Deborah; JACKSON, Andrew P.; LEES, Melissa; OFFIAH, Amaka C.; CARLSTON, Colleen M.; CAREY, John C.; STEWART, Grant S.; BACINO, Carlos A.; CAMPEAU, Philippe M.; LEE, BrendanSPONASTRIME dysplasia is an autosomal-recessive spondyloepimetaphyseal dysplasia characterized by spine (spondylar) abnormalities, midface hypoplasia with a depressed nasal bridge, metaphyseal striations, and disproportionate short stature. Scoliosis, coxa vara, childhood cataracts, short dental roots, and hypogammaglobulinemia have also been reported in this disorder. Although an autosomal-recessive inheritance pattern has been hypothesized, pathogenic variants in a specific gene have not been discovered in individuals with SPONASTRIME dysplasia. Here, we identified bi-allelic variants in TONSL, which encodes the Tonsoku-like DNA repair protein, in nine subjects (from eight families) with SPONASTRIME dysplasia, and four subjects (from three families) with short stature of varied severity and spondylometaphyseal dysplasia with or without immunologic and hematologic abnormalities, but no definitive metaphyseal striations at diagnosis. The finding of early embryonic lethality in a Tonsl(-/-) murine model and the discovery of reduced length, spinal abnormalities, reduced numbers of neutrophils, and early lethality in a tonsl(-/-) zebrafish model both support the hypomorphic nature of the identified TONSL variants. Moreover, functional studies revealed increased amounts of spontaneous replication fork stalling and chromosomal aberrations, as well as fewer camptothecin (CPT)-induced RAD51 foci in subject-derived cell lines. Importantly, these cellular defects were rescued upon re-expression of wild-type (WT) TONSL; this rescue is consistent with the hypothesis that hypomorphic TONSL variants are pathogenic. Overall, our studies in humans, mice, zebrafish, and subject-derived cell lines confirm that pathogenic variants in TONSL impair DNA replication and homologous recombination-dependent repair processes, and they lead to a spectrum of skeletal dysplasia phenotypes with numerous extra-skeletal manifestations.
- Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum(2014) SUKALO, Maja; FIEDLER, Ariane; GUZMAN, Celina; SPRANGER, Stephanie; ADDOR, Marie-Claude; MCHEIK, Jiad N.; BENAVENT, Manuel Oltra; COBBEN, Jan M.; GILLIS, Lynette A.; SHEALY, Amy G.; DESHPANDE, Charu; BOZORGMEHR, Bita; EVERMAN, David B.; STATTIN, Eva-Lena; LIEBELT, Jan; KELLER, Klaus-Michael; BERTOLA, Debora Romeo; KARNEBEEK, Clara D. M. van; BERGMANN, Carsten; LIU, Zhifeng; DUEKER, Gesche; REZAEI, Nima; ALKURAYA, Fowzan S.; OGUR, Gonul; ALRAJOUDI, Abdullah; VENEGAS-VEGA, Carlos A.; VERBEEK, Nienke E.; RICHMOND, Erick J.; KIRBIYIK, Ozgur; RANGANATH, Prajnya; SINGH, Ankur; GODBOLE, Koumudi; ALI, Fouad A. M.; ALVES, Cresio; MAYERLE, Julia; LERCH, Markus M.; WITT, Heiko; ZENKER, MartinJohanson-Blizzard syndrome (JBS) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n=29) and a total of 31 novel UBR1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in-frame deletions consistent with the hypothesis that loss of UBR1 protein function is the molecular basis of JBS. There is an association of missense mutations and small in-frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS. For all previously reported and novel UBR1 mutations together with their clinical data, a mutation database has been established at LOVD.