RESUMO
Background: Rett syndrome (RTT) is a rare neurological disorder that primarily affects the females. Most cases of RTT are caused by a de novo mutation in the MECP2 gene located on the X chromosome. About 1000 MECP2 mutations have been found to be associated with RTT. Objective: The present study is aimed at the mutation screening of MECP2 gene in the RTT patients belonging to the south Indian state of Kerala. Materials and Methods: In total 22 girls with a clinical suspicion of RTT were recruited for the study. Exons 2, 3, and 4 of MECP2 were amplified and sequenced. Results: MECP2 mutations were observed in 12 patients. While 7 mutations were pathogenic, 4 were benign. All of the mutations were located in exons 3 and 4 of MECP2, spanning the methyl-CpG DNA binding domain (MBD), transcription repression domain (TRD), and C-terminal domain (CTD) domains of the MECP2 protein. Four novel mutations were identified. There were no mutations in the MECP2 gene of 10 patients with a clinical suspicion of RTT. Conclusions: A recommended screening strategy for RTT is to first look for mutations in exons 3 and 4 of MECP2, followed by exons 1 and 2, testing for large deletions in MECP2, and screening for mutations in genes, such as CDKL5 and FOXG1 that are reported to cause a Rett-like phenotype.
Assuntos
Proteína 2 de Ligação a Metil-CpG , Síndrome de Rett , Éxons/genética , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Mutação/genética , Fenótipo , Síndrome de Rett/diagnóstico , Síndrome de Rett/genéticaRESUMO
Ever since their discovery, the telomeres and the telomerase have been topics of intensive research, first as a mechanism of cellular aging and later as an indicator of health and diseases in humans. By protecting the chromosome ends, the telomeres play a vital role in preserving the information in our genome. Telomeres shorten with age and the rate of telomere erosion provides insight into the proliferation history of cells. The pace of telomere attrition is known to increase at the onset of several pathological conditions. Telomere shortening has been emerging as a potential contributor in the pathogenesis of several neurological disorders including autism spectrum disorders (ASD), schizophrenia, Alzheimer's disease (AD), Parkinson's disease (PD) and depression. The rate of telomere attrition in the brain is slower than that of other tissues owing to the low rate of cell proliferation in brain. Telomere maintenance is crucial for the functioning of stem cells in brain. Taking together the studies on telomere attrition in various neurological disorders, an association between telomere shortening and disease status has been demonstrated in schizophrenia, AD and depression, in spite of a few negative reports. But, studies in ASD and PD have failed to produce conclusive results. The cause-effect relationship between TL and neurological disorders is yet to be elucidated. The factors responsible for telomere erosion, which have also been implicated in the pathogenesis of neurological disorders, need to be explored in detail. Telomerase activation is now being considered as a potential therapeutic strategy for neurological disorders.
Assuntos
Doenças do Sistema Nervoso/genética , Telômero/genética , Telômero/metabolismo , Animais , Southern Blotting , Humanos , Hibridização in Situ Fluorescente , Reação em Cadeia da PolimeraseRESUMO
Neurodegenerative diseases (NDDs) are the result of progressive deterioration of neurons, ultimately leading to disabilities. There is no effective cure for NDDs at present; ongoing therapies are mainly aimed at treating the most bothersome symptoms. Since early treatment is crucial in NDDs, there is an urgent need for specific and sensitive biomarkers that can aid in early diagnosis of these disorders. Recently, altered expression of miRNAs has been implicated in several neurological disorders, including NDDs. miRNA expression has been extensively investigated in the cells, tissues and body fluids of patients with different types of NDDs. The aim of this review is to provide a comprehensive overview of miRNAs as biomarkers and therapeutic targets for NDDs.
Assuntos
Biomarcadores/metabolismo , Doenças Neurodegenerativas/diagnóstico , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/patologia , Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/genética , Ataxia de Friedreich/patologia , Humanos , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Doença de Huntington/patologia , MicroRNAs/metabolismo , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Atrofia Muscular Espinal/diagnóstico , Atrofia Muscular Espinal/genética , Atrofia Muscular Espinal/patologia , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/patologia , Doença de Parkinson/diagnóstico , Doença de Parkinson/genética , Doença de Parkinson/patologia , Doenças Priônicas/diagnóstico , Doenças Priônicas/genética , Doenças Priônicas/patologiaRESUMO
Telomeres are DNA-protein complexes that form protective caps at the termini of chromosomes, maintaining genomic stability. In this review, we provide a comprehensive overview on the usefulness of telomere length (TL) as biomarkers of neurological disorders. The implications of TL in relation to cognitive ability, cognitive aging and cognitive decline in neurodegenerative disorders are also briefly discussed. Our review suggests that at present it is difficult to draw a reliable conclusion regarding the contribution of TL to neurological disorders. Further, it needs to be examined whether leukocyte TL, which is generally considered as a surrogate marker of TL in other tissues, serves as an indicator of central nervous system TL.
