CHONG AE KIM
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Pediatria, Faculdade de Medicina - Docente
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina
LIM/36 - Laboratório de Pediatria Clínica, Hospital das Clínicas, Faculdade de Medicina - Líder
LIM/03 - Laboratório de Medicina Laboratorial, Hospital das Clínicas, Faculdade de Medicina
15 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 15
- Loss of TNR causes a nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus(2020) WAGNER, Matias; LEVY, Jonathan; JUNG-KLAWITTER, Sabine; BAKHTIARI, Somayeh; MONTEIRO, Fabiola; MAROOFIAN, Reza; BIERHALS, Tatjana; HEMPEL, Maja; ELMALEH-BERGES, Monique; KITAJIMA, Joao P.; KIM, Chong A.; SALOMAO, Julia G.; AMOR, David J.; COOPER, Monica S.; PERRIN, Laurence; PIPIRAS, Eva; NEU, Axel; DOOSTI, Mohammad; KARIMIANI, Ehsan G.; TOOSI, Mehran B.; HOULDEN, Henry; JIN, Sheng Chih; SI, Yue C.; RODAN, Lance H.; VENSELAAR, Hanka; KRUER, Michael C.; KOK, Fernando; HOFFMANN, Georg F.; STROM, Tim M.; WORTMANN, Saskia B.; TABET, Anne-Claude; OPLADEN, ThomasPurpose TNR, encoding Tenascin-R, is an extracellular matrix glycoprotein involved in neurite outgrowth and neural cell adhesion, proliferation and migration, axonal guidance, myelination, and synaptic plasticity. Tenascin-R is exclusively expressed in the central nervous system with highest expression after birth. The protein is crucial in the formation of perineuronal nets that ensheath interneurons. However, the role of Tenascin-R in human pathology is largely unknown. We aimed to establish TNR as a human disease gene and unravel the associated clinical spectrum. Methods Exome sequencing and an online matchmaking tool were used to identify patients with biallelic variants in TNR. Results We identified 13 individuals from 8 unrelated families with biallelic variants in TNR sharing a phenotype consisting of spastic para- or tetraparesis, axial muscular hypotonia, developmental delay, and transient opisthotonus. Four homozygous loss-of-function and four different missense variants were identified. Conclusion We establish TNR as a disease gene for an autosomal recessive nonprogressive neurodevelopmental disorder with spasticity and transient opisthotonus and highlight the role of central nervous system extracellular matrix proteins in the pathogenicity of spastic disorders.
- 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
- 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.
- Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals(2023) SAIDA, Ken; MAROOTAIN, Reza; SENGOKU, Toru; MITANI, Tadahiro; PAGNAMENTA, Alistair T.; MARAFI, Dana; ZAKI, Maha S.; O'BRIAN, Thomas J.; KARIMIANI, Ehsan Ghayoor; KAIYRZHANOV, Rauan; TAKIZAWA, Marina; OHORI, Sachiko; LEONG, Huey Yin; AKAY, Gulsen; GALEHDARI, Hamid; ZAMANI, Mina; ROMY, Ratna; CARROLL, Christopher J.; TOOSI, Mehran Beiraghi; ASHRAFZADEH, Farah; IMANNEZHAD, Shima; MALEK, Hadis; AHANGARI, Najmeh; TOMOUM, Hoda; GOWDA, Vykuntaraju K.; SRINIVASAN, Varunvenkat M.; MURPHY, David; DOMINIK, Natalia; ELBENDARY, Hasnaa M.; RAFAT, Karima; YILMAZ, Sanem; KANMAZ, Seda; SERIN, Mine; KRISHNAKUMAR, Deepa; GARDHAM, Alice; MAW, Anna; RAO, Tekki Sreenivasa; ALSUBHI, Sarah; SROUR, Myriam; BUHAS, Daniela; JEWETT, Tamison; GOLDBERG, Rachel E.; SHAMSELDIN, Hanan; FRENGEN, Eirik; MISCEO, Doriana; STROMME, Petter; CERONI, Jose Ricardo Magliocco; KIM, Chong Ae; YESIL, Gozde; SENGENC, Esma; GULER, Serhat; HULL, Mariam; PARNES, Mered; AKTAS, Dilek; ANLAR, Banu; BAYRAM, Yavuz; PEHLIVAN, Davut; POSEY, Jennifer E.; ALAYI, Shahryar; MANSHADI, Seyed Ali Madani; ALZAIDAN, Hamad; AL-OWAIN, Mohammad; ALABDI, Lama; ABDULWAHAB, Ferdous; SEKIGUCHI, Futoshi; HAMANAKA, Kohei; FUJITA, Atsushi; UCHIYAMA, Yuri; MIZUGUCHI, Takeshi; MIYATAKE, Satoko; MIYAKE, Noriko; ELSHAFIE, Reem M.; SALAYEV, Kamran; GULIYEVA, Ulviyya; ALKURAYA, Fowzan S.; GLEESON, Joseph G.; MONAGHAN, Kristin G.; LANGLEY, Katherine G.; YANG, Hui; MOTAVAF, Mahsa; SAFARI, Saeid; ALIPOUR, Mozhgan; OGATA, Kazuhiro; BROWN, Andre E. X.; LUPSKI, James R.; HOULDEN, Henry; MATSUMOTO, NaomichiPurpose: Brain monoamine vesicular transport disease is an infantile-onset movement disorder that mimics cerebral palsy. In 2013, the homozygous SLC18A2 variant, p.Pro387Leu, was first reported as a cause of this rare disorder, and dopamine agonists were efficient for treating affected individuals from a single large family. To date, only 6 variants have been reported. In this study, we evaluated genotype-phenotype correlations in individuals with biallelic SLC18A2 variants.Methods: A total of 42 affected individuals with homozygous SLC18A2 variant alleles were identified. We evaluated genotype-phenotype correlations and the missense variants in the affected individuals based on the structural modeling of rat VMAT2 encoded by Slc18a2, with cytoplasm-and lumen-facing conformations. A Caenorhabditis elegans model was created for functional studies.Results: A total of 19 homozygous SLC18A2 variants, including 3 recurrent variants, were identified using exome sequencing. The affected individuals typically showed global develop-mental delay, hypotonia, dystonia, oculogyric crisis, and autonomic nervous system involve-ment (temperature dysregulation/sweating, hypersalivation, and gastrointestinal dysmotility). Among the 58 affected individuals described to date, 16 (28%) died before the age of 13 years. Of the 17 patients with p.Pro237His, 9 died, whereas all 14 patients with p.Pro387Leu survived. Although a dopamine agonist mildly improved the disease symptoms in 18 of 21 patients (86%), some affected individuals with p.Ile43Phe and p.Pro387Leu showed milder phenotypes and presented prolonged survival even without treatment. The C. elegans model showed behavioral abnormalities. Conclusion: These data expand the phenotypic and genotypic spectra of SLC18A2-related disorders.(c) 2022 American College of Medical Genetics and Genomics.
- Insights from the genetic characterization of central precocious puberty associated with multiple anomalies(2021) CANTON, Ana Pinheiro Machado; KREPISCHI, Ana Cristina Victorino; MONTENEGRO, Luciana Ribeiro; COSTA, Silvia; ROSENBERG, Carla; STEUNOU, Virginie; SOBRIER, Marie-Laure; SANTANA, Lucas; HONJO, Rachel Sayuri; KIM, Chong Ae; ZEGHER, Francis de; IDKOWIAK, Jan; GILLIGAN, Lorna C.; ARLT, Wiebke; FUNARI, Mariana Ferreira de Assis; JORGE, Alexander Augusto de Lima; MENDONCA, Berenice Bilharinho; NETCHINE, Irene; BRITO, Vinicius Nahime; LATRONICO, Ana ClaudiaSTUDY QUESTION: Is there an (epi)genetic basis in patients with central precocious puberty (CPP) associated with multiple anomalies that unmasks underlying mechanisms or reveals novel genetic findings related to human pubertal control? SUMMARY ANSWER: In a group of 36 patients with CPP associated with multiple phenotypes, pathogenic or likely pathogenic (epi)genetic defects were identified in 12 (33%) patients, providing insights into the genetics of human pubertal control. WHAT IS KNOWN ALREADY: A few studies have described patients with CPP associated with multiple anomalies, but without making inferences on causalities of CPP. Genetic-molecular studies of syndromic cases may reveal disease genes or mechanisms, as the presentation of such patients likely indicates a genetic disorder. STUDY DESIGN, SIZE, DURATION: This translational study was based on a genetic-molecular analysis, including genome-wide high throughput methodologies, for searching structural or sequence variants implicated in CPP and DNA methylation analysis of candidate regions. PARTICIPANTS/MATERIALS, SETTING, METHODS: A cohort of 197 patients (188 girls) with CPP without structural brain lesions was submitted to a detailed clinical evaluation, allowing the selection of 36 unrelated patients (32 girls) with CPP associated with multiple anomalies. Pathogenic allelic variants of genes known to cause monogenic CPP (KISS1R, KISS1, MKRN3 and DLK1) had been excluded in the entire cohort (197 patients). All selected patients with CPP associated with multiple anomalies (n = 36) underwent methylation analysis of candidate regions and chromosomal microarray analysis. A subset (n = 9) underwent whole-exome sequencing, due to presenting familial CPP and/or severe congenital malformations and neurocognitive abnormalities. MAIN RESULTS AND THE ROLE OF CHANCE: Among the 36 selected patients with CPP, the more prevalent associated anomalies were metabolic, growth and neurocognitive conditions. In 12 (33%) of them, rare genetic abnormalities were identified: six patients presented genetic defects in loci known to be involved with CPP (14q32.2 and 7q11.23), whereas the other six presented defects in candidate genes or regions. In detail, three patients presented hypomethylation of DLK1/MEG3:IG-DMR (14q32.2 disruption or Temple syndrome), resulting from epimutation (n = 1) or maternal uniparental disomy of chromosome 14 (n = 2). Seven patients presented pathogenic copy number variants: three with de novo 7q11.23 deletions (Williams-Beuren syndrome), three with inherited Xp22.33 deletions, and one with de novo 1p31.3 duplication. Exome sequencing revealed potential pathogenic variants in two patients: a sporadic female case with frameshift variants in TNRC6B and AREL1 and a familial male case with a missense substitution in UGT2B4 and a frameshift deletion in MKKS. LIMITATIONS, REASONS FOR CAUTION: The selection of patients was based on a retrospective clinical characterization, lacking a longitudinal inclusion of consecutive patients. In addition, future studies are needed, showing the long-term (mainly reproductive) outcomes in the included patients, as most of them are not in adult life yet. WIDER IMPLICATIONS OF THE FINDINGS: The results highlighted the relevance of an integrative clinical-genetic approach in the elucidation of mechanisms and factors involved in pubertal control. Chromosome 14q32.2 disruption indicated the loss of imprinting of DLK1 as a probable mechanism of CPP. Two other chromosomal regions (7q11.23 and Xp22.33) represented new candidate loci potentially involved in this disorder of pubertal timing.
- Richieri-Costa-Pereira syndrome: Expanding its phenotypic and genotypic spectrum(2018) BERTOLA, D. R.; HSIA, G.; ALVIZI, L.; GARDHAM, A.; WAKELING, E. L.; YAMAMOTO, G. L.; HONJO, R. S.; OLIVEIRA, L. A. N.; FRANCESCO, R. C. Di; PEREZ, B. A.; KIM, C. A.; PASSOS-BUENO, M. R.Richieri-Costa-Pereira syndrome is a rare autosomal recessive acrofacial dysostosis that has been mainly described in Brazilian individuals. The cardinal features include Robin sequence, cleft mandible, laryngeal anomalies and limb defects. A biallelic expansion of a complex repeated motif in the 5 untranslated region of EIF4A3 has been shown to cause this syndrome, commonly with 15 or 16 repeats. The only patient with mild clinical findings harbored a 14-repeat expansion in 1 allele and a point mutation in the other allele. This proband is described here in more details, as well as is his affected sister, and 5 new individuals with Richieri-Costa-Pereira syndrome, including a patient from England, of African ancestry. This study has expanded the phenotype in this syndrome by the observation of microcephaly, better characterization of skeletal abnormalities, less severe phenotype with only mild facial dysmorphisms and limb anomalies, as well as the absence of cleft mandible, which is a hallmark of the syndrome. Although the most frequent mutation in this study was the recurrent 16-repeat expansion in EIF4A3, there was an overrepresentation of the 14-repeat expansion, with mild phenotypic expression, thus suggesting that the number of these motifs could play a role in phenotypic delineation.
- Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss(2011) SIMPSON, Michael A.; IRVING, Melita D.; ASILMAZ, Esra; GRAY, Mary J.; DAFOU, Dimitra; ELMSLIE, Frances V.; MANSOUR, Sahar; HOLDER, Sue E.; BRAIN, Caroline E.; BURTON, Barbara K.; KIM, Katherine H.; PAULI, Richard M.; AFTIMOS, Salim; STEWART, Helen; KIM, Chong Ae; HOLDER-ESPINASSE, Muriel; ROBERTSON, Stephen P.; DRAKE, William M.; TREMBATH, Richard C.We used an exome-sequencing strategy and identified an allelic series of NOTCH2 mutations in Hajdu-Cheney syndrome, an autosomal dominant multisystem disorder characterized by severe and progressive bone loss. The Hajdu-Cheney syndrome mutations are predicted to lead to the premature truncation of NOTCH2 with either disruption or loss of the C-terminal proline-glutamate-serine-threonine-rich proteolytic recognition sequence, the absence of which has previously been shown to increase Notch signaling.
- Autosomal dominant frontometaphyseal dysplasia: Delineation of the clinical phenotype(2017) WADE, Emma M.; JENKINS, Zandra A.; DANIEL, Philip B.; MORGAN, Tim; ADDOR, Marie C.; ADES, Lesley C.; BERTOLA, Debora; BOHRING, Axel; CARTER, Erin; CHO, Tae-Joon; GEUS, Christa M. de; DUBA, Hans-Christoph; FLETCHER, Elaine; HADZSIEV, Kinga; HENNEKAM, Raoul C. M.; KIM, Chong A.; KRAKOW, Deborah; MORAVA, Eva; NEUHANN, Teresa; SILLENCE, David; SUPERTI-FURGA, Andrea; VEENSTRA-KNOL, Hermine E.; WIECZOREK, Dagmar; WILSON, Louise C.; MARKIE, David M.; ROBERTSON, Stephen P.Frontometaphyseal dysplasia (FMD) is caused by gain-of-function mutations in the X-linked gene FLNA in approximately 50% of patients. Recently we characterized an autosomal dominant form of FMD (AD-FMD) caused by mutations in MAP3K7, which accounts for the condition in the majority of patients who lack a FLNA mutation. We previously also described a patient with a de novo variant in TAB2, which we hypothesized was causative of another form of AD-FMD. In this study, a cohort of 20 individuals with AD-FMD is clinically evaluated. This cohort consists of 15 individuals with the recently described, recurrent mutation (c.1454C>T) in MAP3K7, as well as three individuals with missense mutations that result in substitutions in the N-terminal kinase domain of TGF beta-activated kinase 1 (TAK1), encoded by MAP3K7. Additionally, two individuals have missense variants in the gene TAB2, which encodes a protein with a close functional relationship to TAK1, TAK1-associated binding protein 2 (TAB2). Although the X-linked and autosomal dominant forms of FMD are very similar, there are distinctions to be made between the two conditions. Individuals with AD-FMD have characteristic facial features, and are more likely to be deaf, have scoliosis and cervical fusions, and have a cleft palate. Furthermore, there are features only found in AD-FMD in our review of the literature including valgus deformity of the feet and predisposition to keloid scarring. Finally, intellectual disability is present in a small number of subjects with AD-FMD but has not been described in association with X-linked FMD.