Assuntos
Predisposição Genética para Doença/genética , Glucosilceramidase/genética , Doença de Parkinson/genética , Polimorfismo de Nucleotídeo Único/genética , Adulto , Fatores Etários , Idoso , Brasil/epidemiologia , Análise Mutacional de DNA , Feminino , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
Point mutations and genomic rearrangements in the MECP2 gene are the major cause of Rett syndrome (RTT), a pervasive developmental disorder affecting almost exclusively females. MECP2 mutations were also identified in patients with autism without RTT. In this study, we present a mutational and gene dosage analysis of the MECP2 in a cohort of 60 Brazilian males with autistic features but not RTT. No duplication or deletion was identified. Sequencing analysis, however, revealed four MECP2 sequence variations. Three of them were previously discussed as non disease causing mutations and one mutation (p.T160S) was novel. It affects a highly conserved amino acid located within the MBD domain, a region of the protein involved in specific recognition and interaction with methylated CpG dinucleotides. The p.T160S variation was not found in the control sample. This mutation may represent a potential genetic factor for autistic phenotype and should be object of further studies.
Assuntos
Transtorno Autístico/genética , Proteína 2 de Ligação a Metil-CpG/genética , Mutação de Sentido Incorreto/genética , Brasil , Criança , Ilhas de CpG/genética , Análise Mutacional de DNA , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/químicaRESUMO
In the last decade, several genes have been linked to Parkinson's disease (PD), including GIGYF2, ATP13A2 and GBA. To explore whether mutations in these genes contribute to development of PD in the Brazilian population, we screened 110 patients with early-onset PD. No clearly pathogenic mutations were identified in ATP13A2 and GIGYF2. In contrast, we identified a significantly higher frequency of known pathogenic mutations in GBA gene among the PD cases (6/110=5.4%) when compared to the control group (0/155) (P=0.0047). Our results strongly support an association between GBA gene mutations and an increased risk of PD. Mutations in GIGYF2 and ATP13A2 do not seem to represent a risk factor to the development of PD in the Brazilian population. Considering the scarcity of studies on GIGYF2, ATP13A2 and GBA mutation frequency in Latin American countries, we present significant data about the contribution of these genes to PD susceptibility.
Assuntos
Proteínas de Transporte/genética , Glucosilceramidase/genética , Doença de Parkinson/genética , Doença de Parkinson/metabolismo , ATPases Translocadoras de Prótons/genética , Fatores Etários , Idoso , Brasil/etnologia , Análise Mutacional de DNA/métodos , Feminino , Predisposição Genética para Doença/genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Parkinson/enzimologia , Fatores de RiscoRESUMO
MeCP2 is a protein that functions as a key factor in epigenetic transcriptional regulation. Mutations in MECP2 gene have been reported as being the major cause of Rett syndrome. These mutations may also cause a wide spectrum of neurological disorders in males. Here, we report the identification of the mutation p.P405L in a 19-year-old Brazilian male with mental retardation. This variant is localized in a highly conserved aminoacid from the carboxy terminal domain and may affect the protein function. Segregation analysis on the patient's mother revealed that this is a de novo mutation and it was not identified in the control sample. The programs SIFT, PolyPhen and A-GVGD considered that the p.P405L may be damaging. Despite the high frequency of non pathogenic variants that have been identified in this gene, our data lead us to consider the p.P405L a disease-causing mutation.
Assuntos
Deficiência Intelectual/genética , Proteína 2 de Ligação a Metil-CpG/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Transtorno do Deficit de Atenção com Hiperatividade/genética , Sequência Conservada , Face/fisiopatologia , Humanos , Masculino , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação , Isoformas de Proteínas , Transtorno de Movimento Estereotipado/genética , Adulto JovemRESUMO
MeCP2 is a protein that selectively binds to methylated cytosines through its methyl-CpG-binding domain (MBD) and connects DNA methylation to transcriptional repression. Mutations in MECP2 gene, located in Xq28, have been reported as being the major cause of Rett syndrome and are also associated with some cases of X-linked mental retardation in both males and females. In this study, we present the first screening in the MECP2 gene in a Brazilian cohort of 239 unrelated males with idiopathic mental retardation. Eight sequence variations were observed in 10 patients: one novel putative pathogenic variant, two never described variants of unknown pathogenic value and five non-pathogenic variations. We conclude that in mentally retarded Brazilian males, non-pathogenic variants in the MECP2 gene are more common than actual pathogenic mutations, and therefore alterations in this gene have a weak relationship with mental retardation in males.