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
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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.
conferenceObject Haploidentical stem cell transplantation with post-transplant Cyclophosphamide for patients with X-Linked Adrenoleukodystrophy and severe aplastic anemia: retrospective analysis(2015) ESTEVES, I.; FERNANDES, J.; RIBEIRO, A.; SANTOS, F.; KONDO, A.; BONFIM, C.; KOK, F.; VARGAS, J.; MANTOVANI, L. Fernando; RODRIGUES, M.; BUB, C. Bonet; KERBAUY, F.; HAMERSCHLAK, N.- Chronic stage of Marchiafava-Bignami disease(2015) LUCATO, Leandro Tavares; FREUA, Fernando; KOK, Fernando
- 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.
- Leukodystrophy with premature ovarian failure: think on vanishing white matter disease (VWMD)(2015) FREUA, Fernando; PARMERA, Jacy Bezerra; DORIA, Denise de Oliveira; PAIVA, Anderson Rodrigues Brandao de; MACEDO-SOUZA, Lucia Ines; KOK, Fernando
- Does MRS Lactate Peak Correlate with Lactate in the CSF and Blood?(2015) SHIBAO, Simone; OTADUY, Maria C. G.; KOK, Fernando; LEITE, Claudia C.Purpose Cerebrospinal fluid (CSF) or brain parenchyma lactate detection is important for the diagnosis of some diseases with aerobic cellular metabolism compromise. Our purpose is to correlate intraventricular magnetic resonance spectroscopy (MRS) lactate detection and quantification to CSF and blood lactate concentration. Methods Twenty-one patients (13 females; mean age 5 years) suspected of having mitochondrial disorders underwent proton MRS with point-resolved spectroscopy (TE = 144 ms). The volume of interest was positioned in the lateral ventricles, and LCModel was used for the MRS lactate peak detection and quantification. CSF and venous blood samples were obtained for lactate quantification immediately after MRS. Comparisons between MRS, CSF, and blood lactate detection and quantification were performed. p < 0.05 was considered significant. Results In our series, CSF lactate levels were high in 11 patients (52%) and blood serum lactate levels were high in 3 patients (14%). MRS was able to detect a lactate peak in all patients. A positive correlation between MRS lactate quantification and CSF lactate was observed (Pearson correlation coefficient = 0.750; p < 0.0001). Blood lactate did not correlate with lactate levels in the lateral ventricle measured by MRS or direct determinations of CSF lactate concentration. When noting the lactate quantification obtained by MRS, only 8 patients (as opposed to 14) presented higher values than the established normality threshold of 1.7 mmol/L. Considering CSF puncture concentration as the gold standard, we obtained 64% of sensitivity and 90% of specificity for MRS quantification. Conclusion If MRS shows increased lactate levels in the ventricles, CSF puncture is not needed for lactate increase confirmation.
- Ataxia and progressive myoclonic epilepsy associated with reduced ceramide synthase 1 (CERS1)(2015) AFONSO, C. O. M.; CAMPOS, M. L. S.; MENDES, V. L.; CAMPELO, C. L. C.; CAMILO, A. F. C.; CORREIA, C. E. R.; FIGUEIREDO, M. M.; KOK, F.; JUNIOR, C. O. G.
- Expanding the Molecular and Clinical Phenotype of SSR4-CDG(2015) NG, Bobby G.; RAYMOND, Kimiyo; KIRCHER, Martin; BUCKINGHAM, Kati J.; WOOD, Tim; SHENDURE, Jay; NICKERSON, Deborah A.; BAMSHAD, Michael J.; WONG, Jonathan T. S.; MONTEIRO, Fabiola Paoli; GRAHAM, Brett H.; JACKSON, Sheryl; SPARKES, Rebecca; SCHEUERLE, Angela E.; CATHEY, Sara; KOK, Fernando; GIBSON, James B.; FREEZE, Hudson H.Congenital disorders of glycosylation (CDG) are a group of mostly autosomal recessive disorders primarily characterized by neurological abnormalities. Recently, we described a single CDG patient with a de novo mutation in the X-linked gene, Signal Sequence Receptor 4 (SSR4). We performed whole-exome sequencing to identify causal variants in several affected individuals who had either an undifferentiated neurological disorder or unsolved CDG of unknown etiology based on abnormal transferrin glycosylation. We now report eight affected males with either de novo (4) or inherited (4) loss of function mutations in SSR4. Western blot analysis revealed that the mutations caused a complete loss of SSR4 protein. In nearly all cases, the abnormal glycosylation of serum transferrin was only slightly above the accepted normal cutoff range.
bookPart Encefalopatias Progressivas em Crianças(2015) BUENO, Clarissa; KOK, Fernando- Here comes the sun: the era of genetics(2015) KOK, Fernando