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
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
BACKGROUND: In a genome-wide association study of autism, zinc finger protein 804A (ZNF804A) single nucleotide polymorphisms (SNPs) were found to be nominally associated in verbally deficient individuals with autism. Zinc finger protein 804A copy number variations (CNVs) have also been observed in individuals with autism. In addition, ZNF804A is known to be involved in theory of mind (ToM) tasks, and ToM deficits are deemed responsible for the communication and social challenges faced by individuals with autism. We hypothesized that ZNF804A could be a risk gene for autism. METHODS: We examined the genetic association and CNVs of ZNF804A in 841 families in which 1 or more members had autism. We compared the expression of ZNF804A in the postmortem brains of individuals with autism (n = 8) and controls (n = 13). We also assessed in vitro the effect of ZNF804A silencing on the expression of several genes known to be involved in verbal efficiency and social cognition. RESULTS: We found that rs7603001 was nominally associated with autism (p = 0.018). The association was stronger (p = 0.008) in the families of individuals with autism who were verbally deficient (n = 761 families). We observed ZNF804A CNVs in 7 verbally deficient boys with autism. In ZNF804A knockdown cells, the expression of synaptosomal-associated protein, 25kDa (SNAP25) was reduced compared with controls (p = 0.009). The expression of ZNF804A (p = 0.009) and SNAP25 (p = 0.009) were reduced in the anterior cingulate gyrus (ACG) of individuals with autism. There was a strong positive correlation between the expression of ZNF804A and SNAP25 in the ACG (p < 0.001). LIMITATIONS: Study limitations include our small sample size of postmortem brains. CONCLUSION: Our results suggest that ZNF804A could be a potential candidate gene mediating the intermediate phenotypes associated with verbal traits in individuals with autism.
