RESUMO
X-linked dystonia-parkinsonism (XDP) is a severe neurodegenerative disorder that manifests as adult-onset dystonia combined with parkinsonism. A SINE-VNTR-Alu (SVA) retrotransposon inserted in an intron of the TAF1 gene reduces its expression and alters splicing in XDP patient-derived cells. As a consequence, increased levels of the TAF1 intron retention transcript TAF1-32i can be found in XDP cells as compared to healthy controls. Here, we investigate the sequence of the deep intronic region included in this transcript and show that it is also present in cells from healthy individuals, albeit in lower amounts than in XDP cells, and that it undergoes degradation by nonsense-mediated mRNA decay. Furthermore, we investigate epigenetic marks (e.g., DNA methylation and histone modifications) present in this intronic region and the spanning sequence. Finally, we show that the SVA evinces regulatory potential, as demonstrated by its ability to repress the TAF1 promoter in vitro. Our results enable a better understanding of the disease mechanisms underlying XDP and transcriptional alterations caused by SVA retrotransposons.
Assuntos
Distúrbios Distônicos/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Transtornos Parkinsonianos/genética , Retroelementos/genética , Transcrição Gênica/genética , Adolescente , Adulto , Metilação de DNA/genética , Feminino , Histona Acetiltransferases/genética , Humanos , Íntrons/genética , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas/genética , Elementos Nucleotídeos Curtos e Dispersos/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Fator de Transcrição TFIID/genética , Adulto JovemRESUMO
BACKGROUND: X-linked dystonia-parkinsonism (XDP) is a rare movement disorder characterized by profound neurodegeneration in the basal ganglia. The molecular consequences and the bioenergetic state of affected individuals remain largely unexplored. OBJECTIVES: To investigate the bioenergetic state in male patients with XDP and female carriers using 31phosphorus magnetic resonance spectroscopy imaging and to correlate these findings with clinical manifestations. METHODS: We examined the levels of high-energy phosphorus-containing metabolites (HEP) in the basal ganglia and cerebellum of five male patients with XDP, 10 asymptomatic female heterozygous carriers, and 10 SVA-insertion-free controls. RESULTS: HEP levels were reduced in the basal ganglia of patients with XDP (PwXDP) compared to controls, but increased in the cerebellum of both male patients and female carriers. CONCLUSIONS: Our findings suggest a potential compensatory mechanism in the cerebellum of female carriers regardless of sex. Our study highlights alterations in HEP levels in PwXDP patients and female carriers.
Assuntos
Gânglios da Base , Cerebelo , Distúrbios Distônicos , Doenças Genéticas Ligadas ao Cromossomo X , Heterozigoto , Humanos , Feminino , Masculino , Distúrbios Distônicos/genética , Distúrbios Distônicos/metabolismo , Distúrbios Distônicos/diagnóstico por imagem , Distúrbios Distônicos/fisiopatologia , Distúrbios Distônicos/patologia , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/metabolismo , Doenças Genéticas Ligadas ao Cromossomo X/fisiopatologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Adulto , Pessoa de Meia-Idade , Gânglios da Base/metabolismo , Gânglios da Base/diagnóstico por imagem , Cerebelo/metabolismo , Cerebelo/diagnóstico por imagem , Cerebelo/patologia , Espectroscopia de Ressonância Magnética , Adulto Jovem , Metabolismo EnergéticoRESUMO
BACKGROUND: X-linked dystonia-parkinsonism (XDP), a neurodegenerative movement disorder endemic to the Philippines, is primarily investigated in patients from Panay Island and the Greater Manila area. However, individuals residing in geographically distant regions may exhibit different clinical or genetic characteristics compared to those documented in earlier reports. OBJECTIVE: The aim was to investigate the relationship of XDP clinical features in a Mindanao cohort with modifiers of age at onset (AAO) variability and utilization of a previously reported AAO model. METHODS: We investigated clinical and genetic features in 27 XDP patients from southern Mindanao. In all patients, we genotyped the 4 polymorphisms linked to AAO. RESULTS: The XDP-relevant hexanucleotide repeat number significantly correlated with AAO in the 27 patients and explained about 68% of AAO variability. There is no statistical difference between the predicted and actual AAO. CONCLUSION: The AAO model may provide reliable predictions by employing the effect of XDP genetic modifiers of AAO variability.