OSORIO LOPES ABATH NETO
Projetos de Pesquisa
Unidades Organizacionais
Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina
4 resultados
Resultados de Busca
Agora exibindo 1 - 4 de 4
- A common CHRNE mutation in Brazilian patients with congenital myasthenic syndrome(2018) ESTEPHAN, Eduardo de Paula; SOBREIRA, Claudia Ferreira da Rosa; SANTOS, Andre Cleriston Jose dos; TOMASELLI, Pedro Jose; MARQUES JR., Wilson; ORTEGA, Roberta Paiva Magalhes; COSTA, Marcela Camara Machado; SILVA, Andre Macedo Serafim da; MENDONCA, Rodrigo Holanda; CALDAS, Vitor Marques; ZAMBON, Antonio Alberto; ABATH NETO, Osorio; MARCHIORI, Paulo Euripedes; HEISE, Carlos Otto; REED, Umbertina Conti; AZUMA, Yoshiteru; TOPF, Ana; LOCHMULLER, Hanns; ZANOTELI, EdmarThe most common causes of congenital myasthenic syndromes (CMS) are CHRNE mutations, and some pathogenic allelic variants in this gene are especially frequent in certain ethnic groups. In the southern region of Brazil, a study found the c.130dupG CHRNE mutation in up to 33% of families with CMS. Here, we aimed to verify the frequency of this mutation among individuals with CMS in a larger cohort of CMS patients from different areas of Brazil and to characterize clinical features of these patients. Eighty-four patients with CMS, from 72 families, were clinically evaluated and submitted to direct sequencing of the exon 2 of CHRNE. The c.130dupG mutation was found in 32 patients (23 families), with 26 patients (19 families, 26.3%) in homozygosis, confirming its high prevalence in different regions of Brazil. Among the homozygous patients, the following characteristics were frequent: onset of symptoms before 2 years of age (92.3%), little functional restriction (92.3%), fluctuating symptoms (100%), ocular muscle impairment (96.1%), ptosis (100%), limb weakness (88.4%), response to pyridostigmine (100%), facial involvement (77%), and bulbar symptoms (70.8%). The pretest probability of finding at least one allele harbouring the c.130dupG mutation was 38.1%. Selecting only patients with impaired eye movement together with limb weakness and improvement with pyridostigmine, the probability increases to 72.2%. This clinical pre-selection of patients is likely a useful tool for regions where CHRNE mutations have a founder effect. In conclusion, the CHRNE mutation c.130dupG leads to fairly benign natural course of the disease with relative homogeneity.
- Recessive congenital fiber type disproportion caused by TPM3 mutation(2018) MORENO, C.; ESTEPHAN, E.; ABATH NETO, O.; CAMELO, C.; SILVA, A.; REED, U.; BONNEMANN, C.; ZANOTELI, E.
- Exome Sequencing Identifies a Novel Nonsense Mutation of MYO6 as the Cause of Deafness in a Brazilian Family(2018) SAMPAIO-SILVA, Juliana; BATISSOCO, Ana Carla; JESUS-SANTOS, Rafaela; ABATH-NETO, Osorio; SCARPELLI, Luciano Cesar; NISHIMURA, Patricia Yoshie; GALINDO, Layla Testa; BENTO, Ricardo Ferreira; OITICICA, Jeanne; LEZIROVITZ, KarinaWe investigated 313 unrelated subjects who presented with hearing loss to identify the novel genetic causes of this condition in Brazil. Causative GJB2/GJB6 mutations were found in 12.7% of the patients. Among the familial cases (100/313), four were selected for exome sequencing. In one case, two novel heterozygous variants were found and were predicted to be pathogenic based on bioinformatics tools, that is, p.Ser906* (MYO6) and p.Arg42Cys (GJB3). We confirmed that this nonsense MYO6 mutation segregated with deafness in this family. Only the proband and her unaffected mother exhibited the GJB3 mutation, which is in the same amino acid of a known Erythrokeratodermia variabilis mutation. None of the patients exhibited this skin disease, but the proband exhibited a more severe hearing loss. Hence, the GJB3 mutation was considered to be a variant of uncertain significance. In conclusion, we described a novel nonsense MYO6 mutation that was responsible for the hearing loss in a Brazilian family. This mutation resides in the neck domain of myosin-VI after the motor domain. Thus, our data give further support for genotype-phenotype correlations, which state that when the motor domain of the protein is functioning, the hearing loss is milder and has a later onset. The three remaining families without mutations in the known genes suggest that there are still deafness genes to be revealed.
- STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility(2018) ZAHARIEVA, Irina T.; SARKOZY, Anna; MUNOT, Pinki; MANZUR, Adnan; O'GRADY, Gina; RENDU, John; MALFATTI, Eduardo; AMTHOR, Helge; SERVAIS, Laurent; URTIZBEREA, J. Andoni; ABATH NETO, Osorio; ZANOTELI, Edmar; DONKERVOORT, Sandra; TAYLOR, Juliet; DIXON, Joanne; POKE, Gemma; FOLEY, A. Reghan; HOLMES, Chris; WILLIAMS, Glyn; HOLDER, Muriel; YUM, Sabrina; MEDNE, Livija; QUIJANO-ROY, Susana; ROMERO, Norma B.; FAURE, Julien; FENG, Lucy; BASTAKI, Laila; DAVIS, Mark R.; PHADKE, Rahul; SEWRY, Caroline A.; BONNEMANN, Carsten G.; JUNGBLUTH, Heinz; BACHMANN, Christoph; TREVES, Susan; MUNTONI, FrancescoSH3 and cysteine-rich domain-containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation-contraction coupling (ECC) machinery, though its role and function are not yet completely understood. Here, we report 18 patients carrying a homozygous p.(Trp284Ser) STAC3 variant in addition to a patient compound heterozygous for the p.(Trp284Ser) and a novel splice site change (c.997-1G > T). Clinical severity ranged from prenatal onset with severe features at birth, to a milder and slowly progressive congenital myopathy phenotype. A malignant hyperthermia (MH)-like reaction had occurred in several patients. The functional analysis demonstrated impaired ECC. In particular, KCl-induced membrane depolarization resulted in significantly reduced sarcoplasmic reticulum Ca2+ release. Co-immunoprecipitation of STAC3 with Ca(V)1.1 in patients and control muscle samples showed that the protein interaction between STAC3 and Ca(V)1.1 was not significantly affected by the STAC3 variants. This study demonstrates that STAC3 gene analysis should be included in the diagnostic work up of patients of any ethnicity presenting with congenital myopathy, in particular if a history of MH-like episodes is reported. While the precise pathomechanism remains to be elucidated, our functional characterization of STAC3 variants revealed that defective ECC is not a result of Ca(V)1.1 sarcolemma mislocalization or impaired STAC3-Ca(V)1.1 interaction.