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
25 resultados
Resultados de Busca
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- Homozygous missense mutation in MED25 segregates with syndromic intellectual disability in a large consanguineous family(2015) FIGUEIREDO, Thalita; MELO, Uira Souto; PESSOA, Andre Luiz Santos; NOBREGA, Paulo Ribeiro; KITAJIMA, Joao Paulo; CORREA, Igor; ZATZ, Mayana; KOK, Fernando; SANTOS, SilvanaBackground Intellectual disability (ID) is a highly heterogeneous condition affecting 2% of the population worldwide. In a field study conducted in a highly inbred area of Northeastern Brazil, we investigated a consanguineous family in which seven adults presented syndromic ID. Methods Genome-Wide Human SNP Array 6.0 (Affymetrix) microarray was used to determine regions of homozygosity-by-descent and whole exome sequencing (WES) was performed in one affected individual using Extended Nextera Rapid-Capture Exome and Illumina HiSeq2500. Results We found two regions with an logarithm of the odds (LOD) score of 3.234: a region spanning 4.0 Mb in 19q13.32-q13.33 and a pericentromeric 20 Mb area in chromosome 2 (2p12-q11.2). WES disclosed in the critical region of chromosome 19 a homozygous variant (c.418C> T, p.Arg140Trp) in Mediator complex subunit 25 (MED25), predicted as deleterious by PolyPhen-2, Provean, Mutation Taster and Sorting Intolerant From Tolerant (SIFT). MED25 is a component of the Mediator complex, involved in regulation of transcription of nearly all RNA polymerase II-dependent genes. Deleterious mutations in MED12, MED17 and MED23 have already been associated with ID. Conclusions These findings demonstrate that the combination of field investigation of families in highly inbred regions with modern technologies is an effective way for identifying new genes associated with ID.
- 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.
- Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations(2020) MONTEIRO, Fabiola P.; CURRY, Cynthia J.; HEVNER, Robert; ELLIOTT, Stephen; FISHER, Jamie H.; TUROCY, John; DOBYNS, William B.; COSTA, Larissa A.; FREITAS, Erika; KITAJIMA, Joao Paulo; KOK, FernandoThe Na+/K+ - ATPase acts as an ion pump maintaining the essential plasma membrane potential in all mammalian cell types, and is essential for many cellular functions. There are four a isoforms (alpha 1, alpha 2, alpha 3 and alpha 4) with distinct expression patterns, kinetic properties and substrate affinity. The alpha 2-isoform is encoded by ATP1A2 and evidence supports its utmost importance in Cl- homeostasis in neurons, and in the function of respiratory neurons at birth. Monallelic pathogenic variants in ATP1A2 are associated with familial hemiplegic migraine type 2 (FHM2) and on rare occasions with alternating hemiplegia of childhood 1 (AHC1). To date, no instances of biallelic loss of function variants have been reported in humans. However, Atp1a2 homozygous loss of function knockout mice (alpha 2(-/-) mice) show severe motor deficits, with lack of spontaneous movements, and are perinatally lethal due to absent respiratory activity. In this report we describe three newborns from two unrelated families, who died neonatally, presenting in utero with an unusual form of fetal hydrops, seizures and polyhydramnios. At birth they had multiple joint contractures (e.g. arthrogryposis), microcephaly, malformations of cortical development, dysmorphic features and severe respiratory insufficiency. Biallelic loss of function variants in ATP1A2, predicted to be pathogenic were found on whole exome sequencing. We propose that this is a distinctive new syndrome caused by complete absence of Na+/K+ - ATPase alpha 2-isoform expression.
- Chromosomal microarray analysis in the genetic evaluation of 279 patients with syndromic obesity(2018) D'ANGELO, Carla Sustek; VARELA, Monica Castro; CASTRO, Claudia Irene Emilio de; OTTO, Paulo Alberto; PEREZ, Ana Beatriz Alvarez; LOURENCO, Charles Marques; KIM, Chong Ae; BERTOLA, Debora Romeo; KOK, Fernando; GARCIA-ALONSO, Luis; KOIFFMANN, Celia PriszkulnikBackground: Syndromic obesity is an umbrella term used to describe cases where obesity occurs with additional phenotypes. It often arises as part of a distinct genetic syndrome with Prader-Willi syndrome being a classical example. These rare forms of obesity provide a unique source for identifying obesity-related genetic changes. Chromosomal microarray analysis (CMA) has allowed the characterization of new genetic forms of syndromic obesity, which are due to copy number variants (CNVs); however, CMA in large cohorts requires more study. The aim of this study was to characterize the CNVs detected by CMA in 279 patients with a syndromic obesity phenotype. Results: Pathogenic CNVs were detected in 61 patients (22%) and, among them, 35 had overlapping/recurrent CNVs. Genomic imbalance disorders known to cause syndromic obesity were found in 8.2% of cases, most commonly deletions of 1p36, 2q37 and 17p11.2 (5.4%), and we also detected deletions at 1p21.3, 2p25.3, 6q16, 9q34, 16p11.2 distal and proximal, as well as an unbalanced translocation resulting in duplication of the GNB3 gene responsible for a syndromic for of childhood obesity. Deletions of 9p terminal and 22q11.2 proximal/distal were found in 1% and 3% of cases, respectively. They thus emerge as being new putative obesity-susceptibility loci. We found additional CNVs in our study that overlapped with CNVs previously reported in cases of syndromic obesity, including a new case of 13q34 deletion (CHAMP1), bringing to 7 the number of patients in whom such defects have been described in association with obesity. Our findings implicate many genes previously associated with obesity (e.g. PTBP2, TMEM18, MYT1L, POU3F2, SIM1, SH2B1), and also identified other potentially relevant candidates including TAS1R3, ALOX5AP, and GAS6. Conclusion: Understanding the genetics of obesity has proven difficult, and considerable insight has been obtained from the study of genomic disorders with obesity associated as part of the phenotype. In our study, CNVs known to be causal for syndromic obesity were detected in 8.2% of patients, but we provide evidence for a genetic basis of obesity in as many as 14% of cases. Overall, our results underscore the genetic heterogeneity in syndromic forms of obesity, which imposes a substantial challenge for diagnosis.
- Clinical aspects of hereditary spastic paraplegia 76 and novel CAPN1 mutations(2018) MELO, U. S.; FREUA, F.; LYNCH, D. S.; RIPA, B. D.; TENORIO, R. B.; SAUTE, J. A. M.; LEITE, F. de Souza; KITAJIMA, J.; HOULDEN, H.; ZATZ, M.; KOK, F.
- A defect in the RNA-processing protein HNRPDL causes limb-girdle muscular dystrophy 1G (LGMD1G)(2014) VIEIRA, Natassia M.; NASLAVSKY, Michel S.; LICINIO, Luciana; KOK, Fernando; SCHLESINGER, David; VAINZOF, Mariz; SANCHEZ, Nury; KITAJIMA, Joao Paulo; GAL, Lihi; CAVACANA, Natale; SERAFINI, Peter R.; CHUARTZMAN, Silvia; VASQUEZ, Cristina; MIMBACAS, Adriana; NIGRO, Vincenzo; PAVANELLO, Rita C.; SCHULDINER, Maya; KUNKEL, Louis M.; ZATZ, MayanaLimb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetically determined muscle disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. More than 20 genes with autosomal recessive (LGMD2A to LGMD2Q) and autosomal dominant inheritance (LGMD1A to LGMD1H) have been mapped/identified to date. Mutations are known for six among the eight mapped autosomal dominant forms: LGMD1A (myotilin), LGMD1B (lamin A/C), LGMD1C (caveolin-3), LGMD1D (desmin), LGMD1E (DNAJB6), and more recently for LGMD1F (transportin-3). Our group previously mapped the LGMD1G gene at 4q21 in a Caucasian-Brazilian family. We now mapped a Uruguayan family with patients displaying a similar LGMD1G phenotype at the same locus. Whole genome sequencing identified, in both families, mutations in the HNRPDL gene. HNRPDL is a heterogeneous ribonucleoprotein family member, which participates in mRNA biogenesis and metabolism. Functional studies performed in S. cerevisiae showed that the loss of HRP1 (yeast orthologue) had pronounced effects on both protein levels and cell localizations, and yeast proteome revealed dramatic reorganization of proteins involved in RNA-processing pathways. In vivo analysis showed that hnrpdl is important for muscle development in zebrafish, causing a myopathic phenotype when knocked down. The present study presents a novel association between a muscular disorder and a RNA-related gene and reinforces the importance of RNA binding/processing proteins in muscle development and muscle disease. Understanding the role of these proteins in muscle might open new therapeutic approaches for muscular dystrophies.
- Mystery solved after 23 years: M syndrome is PIGT-associated multiple congenital anomalies-hypotonia-seizures syndrome 3(2022) NOBREGA, Paulo Ribeiro; CASTRO, Matheus Augusto Araujo; PAIVA, Anderson Rodrigues Brandao de; KOK, Fernando
- The fructose-1,6-bisphosphatase deficiency and the p.(Lys204ArgfsTer72) variant(2021) PINHEIRO, Franciele Cabral; LIGABUE-BRAUN, Rodrigo; SIQUEIRA, Ana Cecilia Menezes de; MATUELLA, Camila; SOUZA, Carolina Fischinger Moura de; MONTEIRO, Fabiola Paoli; KOK, Fernando; SCHWARTZ, Ida Vanessa Doederlein; SPERB-LUDWIG, FernandaFructose-1,6-bisphosphatase (FBPase) deficiency is a rare inborn error of fructose metabolism caused by pathogenic variants in the FBP1 gene. As gluconeogenesis is affected, catabolic episodes can induce ketotic hypoglycemia in patients. FBP1 analysis is the most commonly used approach for the diagnosis of this disorder. Herein, a Brazilian patient is reported. The proband, a girl born to a consanguineous couple, presented with severe hypoglycemia crisis in the neonatal period. At the age 17 months, presented a new crisis accompanied by metabolic acidosis associated with a feverish episode. Genetic analysis was performed by next-generation sequencing (NGS), identifying the NM_000507.3:c.611_614del variant in homozygosis in the FBP1 gene. In silico analysis and 3D modeling were performed, suggesting that this variant is associated with a loss of sites for substrate and Mg2+ binding and for posttranslational modifications of FBPase. The c.611_614del variant is located in a repetitive region of the FBP1 gene that appears to be a hotspot for mutational events. This frameshift creates a premature termination codon in the last coding exon which escapes the nonsense-mediated decay mechanism, according to in silico analysis. This variant results in an intrinsically disordered protein with loss of substrate recognition and post-translational modification sites.
- The segregation of different submicroscopic imbalances underlying the clinical variability associated with a familial karyotypically balanced translocation(2015) FONSECA, Ana Carolina S.; BONALDI, Adriano; FONSECA, Simone A. S.; OTTO, Paulo A.; KOK, Fernando; BAK, Mads; TOMMERUP, Niels; VIANNA-MORGANTE, Angela M.Background: About 7 % of karyotypically balanced chromosomal rearrangements (BCRs) are associated with congenital anomalies due to gene or regulatory element disruption, and cryptic imbalances on rearranged chromosomes. Rare familial BCRs segregating with clinical features are a powerful source for the identifying of causative genes due to the presence of several affected carriers. Case presentation: We report on a karyotypically balanced translocation t(2;22)(p13;q12.2) associated with variable learning disabilities, and craniofacial and hand dysmorphisms, detected in six individuals in a three-generation family. Combined a-CGH, FISH and mate-pair sequencing revealed a ten-break complex rearrangement, also involving chromosome 5. As the consequence of the segregation of the derivative chromosomes der(2), der(5) and der(22), different imbalances were present in affected and clinically normal family members, thus contributing to the clinical variability. A 6.64 Mb duplication of a 5q23.2-23.3 segment was the imbalance common to all affected individuals. Although LMNB1, implicated in adult-onset autosomal dominant leukodystrophy (ADLD) when overexpressed, was among the 18 duplicated genes, none of the adult carriers manifested ADLD, and LMNB1 overexpression was not detected in the two tested individuals, after qRT-PCR. The ectopic location of the extra copy of the LMBN1 gene on chromosome 22 might have negatively impacted its expression. In addition, two individuals presenting with more severe learning disabilities carried a 1.42 Mb 2p14 microdeletion, with three genes (CEP68, RAB1A and ACTR2), which are candidates for the intellectual impairment observed in the previously described 2p14p15 microdeletion syndrome, mapping to the minimal overlapping deleted segment. A 5p15.1 deletion, encompassing 1.47 Mb, also detected in the family, did not segregate with the clinical phenotype. Conclusion: The disclosing of the complexity of an apparently simple two-break familial rearrangement illustrates the importance of reconstructing the precise structure of derivative chromosomes for establishing genotype-phenotype correlations.
conferenceObject Laboratory proactivity can solve non-diagnostic whole exome sequencing: Probing new genes in old data(2022) VEDOVATO-DOS-SANTOS, Juliana Heather; KITAJIMA, Joao P.; JORDAO, Juliana; FREITAS, Erika L.; RIBEIRO, Mara D. O.; SALOMAO, Julia G.; RAMOS, Luiza L. P.; COSTA, Larissa A.; BISPO, Luciana; MONTI, Fernanda; FREITAS, Caroline; MONTEIRO, Fabiola Paoli; KOK, Fernando
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