GUILHERME LOPES YAMAMOTO
Projetos de Pesquisa
Unidades Organizacionais
Instituto da Criança, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina
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- Mutations in Fibronectin Cause a Subtype of Spondylometaphyseal Dysplasia with ""Corner Fractures''(2017) LEE, Chae Syng; FU, He; BARATANG, Nissan; ROUSSEAU, Justine; KUMRA, Heena; SUTTON, V. Reid; NICETA, Marcello; CIOLFI, Andrea; YAMAMOTO, Guilherme; BERTOLA, Debora; MARCELIS, Carlo L.; LUGTENBERG, Dorien; BARTULI, Andrea; KIM, Choel; HOOVER-FONG, Julie; SOBREIRA, Nara; PAULI, Richard; BACINO, Carlos; KRAKOW, Deborah; PARBOOSINGH, Jillian; YAP, Patrick; KARIMINEJAD, Ariana; MCDONALD, Marie T.; ARACENA, Mariana I.; LAUSCH, Ekkehart; UNGER, Sheila; SUPERTI-FURGA, Andrea; LU, James T.; COHN, Dan H.; TARTAGLIA, Marco; LEE, Brendan H.; REINHARDT, Dieter P.; CAMPEAU, Philippe M.Fibronectin is a master organizer of extracellular matrices (ECMs) and promotes the assembly of collagens, fibrillin-1, and other proteins. It is also known to play roles in skeletal tissues through its secretion by osteoblasts, chondrocytes, and mesenchymal cells. Spondylo-metaphyseal dysplasias (SMDs) comprise a diverse group of skeletal dysplasias and often manifest as short stature, growth-plate irregularities, and vertebral anomalies, such as scoliosis. By comparing the exomes of individuals with SMD with the radiographic appearance of ""corner fractures'' at metaphyses, we identified three individuals with fibronectin (FN1) variants affecting highly conserved residues. Furthermore, using matching tools and the SkelDys emailing list, we identified other individuals with de novo FN1 variants and a similar phenotype. The severe scoliosis in most individuals and rare developmental coxa vara distinguish individuals with FN1 mutations from those with classical Sutcliffe-type SMD. To study functional consequences of these FN1 mutations on the protein level, we introduced three disease-associated missense variants (p.Cys87Phe [c.260G>T], p.Tyr240Asp [c.718T>G], and p.Cys260Gly [c.778T>G]) into a recombinant secreted N-terminal 70 kDa fragment (rF70K) and the full-length fibronectin (rFN). The wild-type rF70K and rFN were secreted into the culture medium, whereas all mutant proteins were either not secreted or secreted at significantly lower amounts. Immunofluorescence analysis demonstrated increased intracellular retention of the mutant proteins. In summary, FN1 mutations that cause defective fibronectin secretion are found in SMD, and we thus provide additional evidence for a critical function of fibronectin in cartilage and bone.
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.- 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.
- 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.
- Mutations in LONP1, a Mitochondrial Matrix Protease, Cause CODAS Syndrome(2015) DIKOGLU, Esra; ALFAIZ, Ali; GORNA, Maria; BERTOLA, Deborah; CHAE, Jong Hee; CHO, Tae-Joon; DERBENT, Murat; ALANAY, Yasemin; GURAN, Tulay; KIM, Ok-Hwa; LLERENAR JR., Juan C.; YAMAMOTO, Guillerme; SUPERTI-FURGA, Giulio; REYMOND, Alexandre; XENARIOS, Ioannis; STEVENSON, Brian; CAMPOS-XAVIER, Belinda; BONAFE, Luisa; SUPERTI-FURGA, Andrea; UNGER, SheilaCerebral, ocular, dental, auricular, skeletal anomalies (CODAS) syndrome (MIM 600373) was first described and named by Shehib et al, in 1991 in a single patient. The anomalies referred to in the acronym are as follows: cerebral-developmental delay, ocular-cataracts, dental-aberrant cusp morphology and delayed eruption, auricular-malformations of the external ear, and skeletal-spondyloepiphyseal dysplasia. This distinctive constellation of anatomical findings should allow easy recognition but despite this only four apparently sporadic patients have been reported in the last 20 years indicating that the full phenotype is indeed very rare with perhaps milder or a typical presentations that are allelic but without sufficient phenotypic resemblance to permit clinical diagnosis. We performed exome sequencing in three patients (an isolated case and a brother and sister sib pair) with classical features of CODAS. Sanger sequencing was used to confirm results as well as for mutation discovery in a further four unrelated patients ascertained via their skeletal features. Compound heterozygous or homozygous mutations in LONP1 were found in all (8 separate mutations; 6 missense, 1 nonsense, 1 small in-frame deletion) thus establishing the genetic basis of CODAS and the pattern of inheritance (autosomal recessive). LONP1 encodes an enzyme of bacterial ancestry that participates in protein turnover within the mitochondrial matrix. The mutations cluster at the ATP-binding and proteolytic domains of the enzyme. Biallelic inheritance and clustering of mutations confirm dysfunction of LONP1 activity as the molecular basis of CODAS but the pathogenesis remains to be explored. (C) 2015 Wiley Periodicals, Inc.