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
12 resultados
Resultados de Busca
Agora exibindo 1 - 10 de 12
- 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.
- Herpetiform keratitis and palmoplantar hyperkeratosis: warning signs for Richner-Hanhart syndrome(2017) SOARES, Diogo C.; STROPARO, Mariana N.; LIAN, Yu C.; TAKAKURA, Cristina Y.; WOLF, Sabrina; BETZ, Regina; KIM, Chong A.Richner-Hanhart syndrome (RHS, tyrosinemia type II) is a rare, autosomal recessive inborn error of tyrosine metabolism caused by tyrosine aminotransferase deficiency. It is characterized by photophobia due to keratitis, painful palmoplantar hyperkeratosis, variable mental retardation, and elevated serum tyrosine levels. Patients are often misdiagnosed with herpes simplex keratitis. We report on a a boy from Brazil who presented with bilateral keratitis secondary to RHS, which had earlier been misdiagnosed as herpes simplex keratitis.
- 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.
- GNPTAB missense mutations cause loss of GlcNAc-1-phosphotransferase activity in mucolipidosis type II through distinct mechanisms(2017) LUDWIG, Nataniel Floriano; VELHO, Renata Voltolini; SPERB-LUDWIG, Fernanda; ACOSTA, Angelina Xavier; RIBEIRO, Erlane Marques; KIM, Chong A.; HOROVITZ, Dafne Dam Gandelman; BOY, Raquel; RODOVALHO-DORIQUI, Maria Juliana; LOURENCO, Charles Marques; SANTOS, Emerson Santana; BRAULKE, Thomas; POHL, Sandra; SCHWARTZ, Ida Vanessa D.Mucolipidoses (ML) II and III alpha/beta are lysosomal storage diseases caused by pathogenic mutations in GNPTAB encoding the alpha/beta-subunit precursor of GlcNAc-1-phosphotransferase. To determine genotype-phenotype correlation and functional analysis of mutant GlcNAc-1-phosphotransferase, 13 Brazilian patients clinically and biochemical diagnosed for MLII or III alpha/beta were studied. By sequencing of genomic GNPTAB of the MLII and MLIII alpha/beta patients we identified six novel mutations: p.D76G, p.S385L, p.Q278Kfs*3, p.H588Qfs*27, p.N642Lfs*10 and p.Y1111*. Expression analysis by western blotting and immunofluorescence microscopy revealed that the mutant alpha/beta-subunit precursor p.D76G is retained in the endoplasmic reticulum whereas the mutant p.S385L is correctly transported to the cis-Golgi apparatus and proteolytically processed. Both mutations lead to complete loss of GlcNAc-1-phosphotransferase activity, consistent with the severe clinical MLII phenotype of the patients. Our study expands the genotypic spectrum of MLII and provides novel insights into structural requirements to ensure GlcNAc-1-phosphotransferase activity.
- Single-Nucleotide Polymorphism Array-Based Characterization of Ring Chromosome 18(2013) SPREIZ, Ana; GUILHERME, Roberta S.; CASTELLAN, Claudio; GREEN, Andrew; RITTINGER, Olaf; WELLEK, Brigitte; UTERMANN, Barbara; ERDEL, Martin; FAUTH, Christine; HABERLANDT, Edda; KIM, Chong A.; KULIKOWSKI, Leslie D.; MELONI, Vera A.; UTERMANN, Gerd; ZSCHOCKE, Johannes; MELARAGNO, Maria I.; KOTZOT, DieterObjective To study genotype-phenotype correlation of ring chromosome 18 [r(18)] in 9 patients with 46, XN karyotype. Study design In 9 patients with a de novo 46, XN, r(18) karyotype (7 females, 2 males), we performed high-resolution single-nucleotide polymorphism array analysis (Illumina Human Omni1-QuadV1 array in 6 patients, Affymetrix 6.0 array in 3 patients), investigation of parental origin, and genotype-phenotype correlation. Results No breakpoint was recurrent. Single metaphases with loss of the ring, double rings, or secondarily rearranged rings were found in some cases, but true mosaicism was present in none of these cases. In 3 patients, additional duplications in 18p (of 1.4 Mb, 2 Mb, and 5.8 Mb) were detected. In 1 patient, an additional deletion of 472 kb in Xp22.33, including the SHOX gene, was found. Parental origin of r(18) was maternal in 2 patients and paternal in 4 patients, and formation was most likely meiotic. Karyotype was normal in all investigated parents (n = 15). At birth, mean maternal age was 30 years (n = 9) and mean paternal age was 34.4 years (n = 9). Conclusion Genotype-phenotype correlation revealed extensive clinical variability but no characteristic r(18) phenotype. Severity of clinical signs were generally correlated with the size of the deletion. Patients with large deletions in 18p and small deletions in 18q exhibited mainly symptoms related to 18p-, whereas those with large deletions in 18q and small deletions in 18p had symptoms of 18q-.
- Steric Clash in the SET Domain of Histone Methyltransferase NSD1 as a Cause of Sotos Syndrome and Its Genetic Heterogeneity in a Brazilian Cohort(2016) HA, Kyungsoo; ANAND, Priya; LEE, Jennifer A.; JONES, Julie R.; KIM, Chong Ae; BERTOLA, Debora Romeo; LABONNE, Jonathan D. J.; LAYMAN, Lawrence C.; WENZEL, Wolfgang; KIM, Hyung-GooMost histone methyltransferases (HMTase) harbor a predicted Su(var)3-9, Enhancer-of-zeste, Trithorax (SET) domain, which transfers a methyl group to a lysine residue in their substrates. Mutations of the SET domains were reported to cause intellectual disability syndromes such as Sotos, Weaver, or Kabuki syndromes. Sotos syndrome is an overgrowth syndrome with intellectual disability caused by haploinsufficiency of the nuclear receptor binding SET domain protein 1 (NSD1) gene, an HMTase at 5q35.2-35.3. Here, we analyzed NSD1 in 34 Brazilian Sotos patients and identified three novel and eight known mutations. Using protein modeling and bioinformatic approaches, we evaluated the effects of one novel (I2007F) and 21 previously reported missense mutations in the SET domain. For the I2007F mutation, we observed conformational change and loss of structural stability in Molecular Dynamics (MD) simulations which may lead to loss-of-function of the SET domain. For six mutations near the ligand-binding site we observed in simulations steric clashes with neighboring side chains near the substrate S-Adenosyl methionine (SAM) binding site, which may disrupt the enzymatic activity of NSD1. These results point to a structural mechanism underlying the pathology of the NSD1 missense mutations in the SET domain in Sotos syndrome. NSD1 mutations were identified in only 32% of the Brazilian Sotos patients in our study cohort suggesting other genes (including unknown disease genes) underlie the molecular etiology for the majority of these patients. Our studies also found NSD1 expression to be profound in human fetal brain and cerebellum, accounting for prenatal onset and hypoplasia of cerebellar vermis seen in Sotos syndrome.
- 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.
- Mutations in SRCAP, Encoding SNF2-Related CREBBP Activator Protein, Cause Floating-Harbor Syndrome(2012) HOOD, Rebecca L.; LINES, Matthew A.; NIKKEL, Sarah M.; SCHWARTZENTRUBER, Jeremy; BEAULIEU, Chandree; NOWACZYK, Malgorzata J. M.; ALLANSON, Judith; KIM, Chong Ae; WIECZOREK, Dagmar; MOILANEN, Jukka S.; LACOMBE, Didier; GILLESSEN-KAESBACH, Gabriele; WHITEFORD, Margo L.; QUAIO, Caio Robledo D. C.; GOMY, Israel; BERTOLA, Debora R.; ALBRECHT, Beate; PLATZER, Konrad; MCGILLIVRAY, George; ZOU, Ruobing; MCLEOD, D. Ross; CHUDLEY, Albert E.; CHODIRKER, Bernard N.; MARCADIER, Janet; MAJEWSKI, Jacek; BULMAN, Dennis E.; WHITE, Susan M.; BOYCOTT, Kym M.Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic MS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome [RTS]). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.
- Johanson-Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation(2014) QUAIO, C. R.; KODA, Y. K.; BERTOLA, D. R.; SUKALO, M.; ZENKER, M.; KIM, C. A.Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disorder resulting from loss-of-function mutations in the UBR1 gene. JBS can be easily recognized by its unique clinical presentation (including exocrine pancreatic insufficiency, hypoplasia/aplasia of the alae nasi, congenital scalp defects, sensorineural hearing loss, growth retardation, psychomotor retardation, and anal and genitourinary anomalies). The objective of this study is to report on the first familial case of gender-discordant twins presenting JBS and a novel mutation in the UBR1 gene. We also review literature describing molecularly confirmed cases of JBS. The female twin developed refractory severe diarrhea after the second month of life and died at the age of 3 months. The male twin also developed diarrhea and failure to thrive after the 3 month of life but improved when nutrition support and pancreatic enzyme replacement was started, and he has survived into adolescence. Both patients presented typical clinical features of JBS. A homozygous nonsense mutation (c.3682C>T; p.Q1228X) in UBR1 was confirmed. Severe presentation of JBS usually involves deleterious (nonsense, frameshift, or splice-site) mutations in the UBR1 gene that are thought to completely abolish the expression of a functional protein product, as in this familial case; however, milder presentation of JBS has occasionally been observed with missense mutations in at least 1 of the 2 copies of UBR1, in which there may be residual activity of the product of this gene. Early diagnosis and adequate treatment are crucial for a favorable outcome.