FERNANDO KOK
Projetos de Pesquisa
Unidades Organizacionais
Departamento de Neurologia, Faculdade de Medicina - Docente
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/15 - Laboratório de Investigação em Neurologia, Hospital das Clínicas, Faculdade de Medicina
4 resultados
Resultados de Busca
Agora exibindo 1 - 4 de 4
- GNBS Mutations Cause an Autosomal-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability(2016) LODDER, Elisabeth M.; NITTIS, Pasquelena De; KOOPMAN, Charlotte D.; WISZNIEWSKI, Wojciech; SOUZA, Carolina Fischinger Moura de; LAHROUCHI, Najim; GUEX, Nicolas; NAPOLIONI, Valerio; TESSADORI, Federico; BEEKMAN, Leander; NANNENBERG, Eline A.; BOUALLA, Lamiae; BLOM, Nico A.; GRAAFF, Wim de; KAMERMANS, Maarten; COCCIADIFERRO, Dario; MALERBA, Natascia; MANDRIANI, Barbara; AKDEMIR, Zeynep Hande Coban; FISH, Richard J.; ELDOMERY, Mohammad K.; RATBI, Ilham; WILDE, Arthur A. M.; BOER, Teun de; SIMONDS, William F.; NEERMAN-ARBEZ, Marguerite; SUTTON, V. Reid; KOK, Fernando; LUPSKI, James R.; REYMOND, Alexandre; BEZZINA, Connie R.; BAKKERS, Jeroen; MERLA, GiuseppeGNB5 encodes the G protein beta subunit 5 and is involved in inhibitory G protein signaling. Here, we report mutations in GNB5 that are associated with heart-rate disturbance, eye disease, intellectual disability, gastric problems, hypotonia, and seizures in nine individuals from six families. We observed an association between the nature of the variants and clinical severity; individuals with loss-of-function alleles had more severe symptoms, including substantial developmental delay, speech defects, severe hypotonia, pathological gastro-esophageal re flux, retinal disease, and sinus-node dysfunction, whereas related heterozygotes harboring missense variants presented with a clinically milder phenotype. Zebrafish gnb5 knockouts recapitulated the phenotypic spectrum of affected individuals, including cardiac, neurological, and ophthalmological abnormalities, supporting a direct role of GNB5 in the control of heart rate, hypotonia, and vision.
- Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction(2021) HOED, Joery den; BOER, Elke de; VOISIN, Norine; DINGEMANS, Alexander J. M.; GUEX, Nicolas; WIEL, Laurens; NELLAKER, Christoffer; AMUDHAVALLI, Shivarajan M.; BANKA, Siddharth; BENA, Frederique S.; BEN-ZEEV, Bruria; BONAGURA, Vincent R.; BRUEL, Ange-Line; BRUNET, Theresa; BRUNNER, Han G.; CHEW, Hui B.; CHRAST, Jacqueline; CIMBALISTIENE, Loreta; COON, Hilary; DELOT, Emmanuelle C.; DEMURGER, Florence; DENOMME-PICHON, Anne-Sophie; DEPIENNE, Christel; DONNAI, Dian; DYMENT, David A.; ELPELEG, Orly; FAIVRE, Laurence; GILISSEN, Christian; GRANGER, Leslie; HABER, Benjamin; HACHIYA, Yasuo; ABEDI, Yasmin Hamzavi; HANEBECK, Jennifer; HEHIR-KWA, Jayne Y.; HORIST, Brooke; ITAI, Toshiyuki; JACKSON, Adam; JEWELL, Rosalyn; JONES, Kelly L.; JOSS, Shelagh; KASHII, Hirofumi; KATO, Mitsuhiro; KATTENTIDT-MOURAVIEVA, Anja A.; KOK, Fernando; KOTZAERIDOU, Urania; KRISHNAMURTHY, Vidya; KUCINSKAS, Vaidutis; KUECHLER, Alma; LAVILLAUREIX, Alinoe; LIU, Pengfei; MANWARING, Linda; MATSUMOTO, Naomichi; MAZEL, Benoit; MCWALTER, Kirsty; MEINER, Vardiella; MIKATI, Mohamad A.; MIYATAKE, Satoko; MIZUGUCHI, Takeshi; MOEY, Lip H.; MOHAMMED, Shehla; MOR-SHAKED, Hagar; MOUNTFORD, Hayley; NEWBURY-ECOB, Ruth; ODENT, Sylvie; OREC, Laura; OSMOND, Matthew; PALCULICT, Timothy B.; PARKER, Michael; PETERSEN, Andrea K.; PFUNDT, Rolph; PREIKSAITIENE, Egle; RADTKE, Kelly; RANZA, Emmanuelle; ROSENFELD, Jill A.; SANTIAGO-SIM, Teresa; SCHWAGER, Caitlin; SINNEMA, Margje; BLOK, Lot Snijders; SPILLMANN, Rebecca C.; STEGMANN, Alexander P. A.; THIFFAULT, Isabelle; Linh Tran; VAKNIN-DEMBINSKY, Adi; VEDOVATO-DOS-SANTOS, Juliana H.; VERGANO, Samantha A. Schrier; VILAIN, Eric; VITOBELLO, Antonio; WAGNER, Matias; WAHEEB, Androu; WILLING, Marcia; ZUCCARELLI, Britton; KINI, Usha; NEWBURY, Dianne F.; KLEEFSTRA, Tjitske; REYMOND, Alexandre; FISHER, Simon E.; VISSERS, Lisenka E. L. M.Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.
- GNBS iviutations Cause an Autosomai-Recessive Multisystem Syndrome with Sinus Bradycardia and Cognitive Disability (vol 99, pg 704, 2016)(2016) LODDER, Elisabeth M.; NITTIS, Pasquelena De; KOOPMAN, Charlotte D.; WISZNIEWSKI, Wojciech; SOUZA, Carolina Fischinger Moura de; LAHROUCHI, Najim; GUEX, Nicolas; NAPOLIONI, Valerio; TESSADORI, Federico; BEEKMAN, Leander; NANNENBERG, Eline A.; BOUALLA, Lamiae; BLOM, Nico A.; GRAAFF, Wim de; KAMERMANS, Maarten; COCCIADIFERRO, Dario; MALERBA, Natascia; MANDRIANI, Barbara; AKDEMIR, Zeynep Hande Coban; FISH, Richard J.; ELDOMERY, Mohammad K.; RATBI, Ilham; WILDE, Arthur A. M.; BOER, Teun de; SIMONDS, William F.; NEERMAN-ARBEZ, Marguerite; SUTTON, V. Reid; KOK, Fernando; LUPSKI, James R.; REYMOND, Alexandre; BEZZINA, Connie R.; BAKKERS, Jeroen; MERLA, Giuseppe
- Paralog Studies Augment Gene Discovery: DDX and DHX Genes(2019) PAINE, Ingrid; POSEY, Jennifer E.; GROCHOWSKI, Christopher M.; JHANGIANI, Shalini N.; ROSENHECK, Sarah; KLEYNER, Robert; MARMORALE, Taylor; YOON, Margaret; WANG, Kai; ROBISON, Reid; CAPPUCCIO, Gerarda; PINELLI, Michele; MAGLI, Adriano; AKDEMIR, Zeynep Coban; HUI, Joannie; YEUNG, Wai Lan; WONG, Bibiana K. Y.; ORTEGA, Lucia; BEKHEIRNIA, Mir Reza; BIERHALS, Tatjana; HEMPEL, Maja; JOHANNSEN, Jessika; SANTER, Rene; AKTAS, Dilek; ALIKASIFOGLU, Mehmet; BOZDOGAN, Sevcan; AYDIN, Hatip; KARACA, Ender; BAYRAM, Yavuz; ITYEL, Hadas; DORSCHNER, Michael; WHITE, Janson J.; WILICHOWSKI, Ekkehard; WORTMANN, Saskia B.; CASELLA, Erasmo B.; KITAJIMA, Joao Paulo; KOK, Fernando; MONTEIRO, Fabiola; MUZNY, Donna M.; BAMSHAD, Michael; GIBBS, Richard A.; SUTTON, V. Reid; ESCH, Hilde Van; BRUNETTI-PIERRI, Nicola; HILDEBRANDT, Friedhelm; BRAUTBAR, Ariel; VEYVER, Ignatia B. Van den; GLASS, Ian; LESSEL, Davor; LYON, Gholson J.; LUPSKI, James R.Members of a paralogous gene family in which variation in one gene is known to cause disease are eight times more likely to also be associated with human disease. Recent studies have elucidated DHX30 and DDX3X as genes for which pathogenic variant alleles are involved in neurodevelopmental disorders. We hypothesized that variants in paralogous genes encoding members of the DExD/H-box RNA helicase superfamily might also underlie developmental delay and/or intellectual disability (DD and/or ID) disease phenotypes. Here we describe 15 unrelated individuals who have DD and/or ID, central nervous system (CNS) dysfunction, vertebral anomalies, and dysmorphic features and were found to have probably damaging variants in DExD/H-box RNA helicase genes. In addition, these individuals exhibit a variety of other tissue and organ system involvement including ocular, outer ear, hearing, cardiac, and kidney tissues. Five individuals with homozygous (one), compound-heterozygous (two), or de novo (two) missense variants in DHX37 were identified by exome sequencing. We identified ten total individuals with missense variants in three other DDX/DHX paralogs: DHX16 (four individuals), DDX54 (three individuals), and DHX34 (three individuals). Most identified variants are rare, predicted to be damaging, and occur at conserved amino acid residues. Taken together, these 15 individuals implicate the DExD/H-box helicases in both dominantly and recessively inherited neurodevelopmental phenotypes and highlight the potential for more than one disease mechanism underlying these disorders.