RESUMEN
Spinocerebellar ataxia type 17 (SCA17) is an autosomal dominant inherited disorder characterized by degeneration of spinocerebellar tracts and selected brainstem neurons owing to the expansion of a CAG repeat of the human TATA-binding protein (hTBP) gene. To gain insight into the pathogenesis of this hTBP mutation, we generated transgenic mice with the mutant hTBP gene driven by the Purkinje specific protein (Pcp2/L7) gene promoter. Mice with the expanded hTBP allele developed ataxia within 2-5 months. Behavioral analysis of L7-hTBP transgenic mice showed reduced fall latency in a rotarod assay. Purkinje cell degeneration was identified by immunostaining of calbindin and IP3R1. Reactive gliosis and neuroinflammation occurred in the transgenic cerebellum, accompanied by up-regulation of GFAP and Iba1. The L7-hTBP transgenic mice were thus confirmed to recapitulate the SCA17 phenotype and were used as a disease model to explore the potential of granulocyte-colony stimulating factor in SCA17 treatment. Our results suggest that granulocyte-colony stimulating factor has a neuroprotective effect in these transgenic mice, ameliorating their neurological and behavioral deficits. These data indicate that the expression of the mutant hTBP in Purkinje cells is sufficient to produce cell degeneration and an ataxia phenotype, and constitutes a good model for better analysis of the neurodegeneration in SCA17.
Asunto(s)
Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Ataxias Espinocerebelosas/genética , Proteína de Unión a TATA-Box/genética , Animales , Femenino , Humanos , Ratones , Ratones Transgénicos , Fenotipo , Ataxias Espinocerebelosas/metabolismo , Ataxias Espinocerebelosas/prevención & control , Proteína de Unión a TATA-Box/uso terapéuticoRESUMEN
BACKGROUND: Spinocerebellar ataxia type 17 (SCA17) involves the expression of a CAG/CAA expansion mutation in the gene encoding TATA-box binding protein (TBP), a general transcription initiation factor. The spectrum of SCA17 clinical presentation is broad. METHODS: We screened for triplet expansion in the TBP gene in Taiwanese Parkinson's disease (PD), Alzheimer's disease (AD) and atypical parkinsonism and investigated the functional implication of expanded alleles using lymphoblastoid cells as a model. RESULTS: A total of 6 mildly expanded alleles (44-46) were identified in patients group. The frequency of the individuals carrying expanded alleles in PD (3/602 [0.5%]), AD (2/245 [0.8%]) and atypical parkinsonism (1/44 [2.3%]) is not significant as compared to that in the control subjects (0/644 [0.0%]). In lymphoblastoid cells, HSPA5, HSPA8 and HSPB1 expression levels in cells with expanded TBP were significantly lower than that of the control cells. Although not significantly, the levels of PARK7 protein isoforms 6.1 and 6.4 are notably increased in SCA17 lymphoblastoid cells. Treatment of TBH (tert-butyl hydroperoxide) significantly increases cell death in the cells with mildly expanded TBP. CONCLUSIONS: Our findings expand the spectrum of SCA17 phenotype and may contribute to our understanding of the disease.
Asunto(s)
Enfermedad de Alzheimer/genética , Predisposición Genética a la Enfermedad/genética , Enfermedad de Parkinson/genética , Secuencias Repetitivas de Ácidos Nucleicos/genética , Proteína de Unión a TATA-Box/genética , Expansión de Repetición de Trinucleótido/genética , Anciano , Alelos , Enfermedad de Alzheimer/fisiopatología , Línea Celular , Estudios de Cohortes , Análisis Mutacional de ADN , Chaperón BiP del Retículo Endoplásmico , Femenino , Humanos , Linfocitos/metabolismo , Masculino , Persona de Mediana Edad , Mutación , Enfermedad de Parkinson/fisiopatología , Reacción en Cadena de la Polimerasa , Sensibilidad y EspecificidadRESUMEN
Netherton syndrome (NS) is a severe autosomal recessive skin disorder characterized by congenital ichthyosiform erythroderma, hair shaft abnormalities, and atopic diathesis. Recently, pathogenic mutations were identified in serine protease inhibitor Kazal-type 5 (SPINK5), the gene that encodes lympho-epithelial Kazal-type related inhibitor (LEKTI), a type of serine protease inhibitor involved in the regulation of skin barrier formation and immunity. In the present report, we describe the mutation analysis of two Taiwanese patients with NS. Patient 1 has heterozygous mutations; the maternal allele has novel T808I (C-T transition in codon 808) and the paternal allele has recurrent R790X (C-T transition in codon 790). Patient 2 is homozygous for a novel polymorphism R267Q (G-A transition in codon 267). The change was not detected in the patient's father. Haplotype analysis revealed that the patient was homozygous for the 5 single nucleotide polymorphisms in the genomic sequence of SPINK5 as well as the flanking (GT)(17) and D5S413, in addition to the discrepancy of R267Q. Nevertheless real-time quantitative PCR analysis revealed no microdeletion in the genomic sequence of SPINK5. Thus uniparental disomy of maternal SPINK5 allele was indicated.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Cabello/anomalías , Eritrodermia Ictiosiforme Congénita/genética , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Niño , Preescolar , Codón sin Sentido/genética , ADN/genética , Análisis Mutacional de ADN/métodos , Femenino , Genes Ligados a X , Predisposición Genética a la Enfermedad/etnología , Haplotipos , Humanos , Hipersensibilidad Inmediata/etnología , Hipersensibilidad Inmediata/genética , Eritrodermia Ictiosiforme Congénita/etnología , Mutación Missense/genética , Polimorfismo de Nucleótido Simple/genética , Inhibidor de Serinpeptidasas Tipo Kazal-5 , Síndrome , TaiwánAsunto(s)
Antitrombinas/genética , Arginina/genética , Trombosis Intracraneal/genética , Trombosis Intracraneal/fisiopatología , Mutación Puntual , Antitrombinas/clasificación , Familia , Femenino , Humanos , Trombosis Intracraneal/diagnóstico por imagen , Masculino , Linaje , Flebografía , Recurrencia , TaiwánRESUMEN
Schizophrenia has a complex and non-Mendelian mode of inheritance. Recently, trinucleotide repeat (TNR)-containing genes have been considered as the candidate genes predisposing to schizophrenia. The purpose of this study was to determine whether a genetic association could be observed between schizophrenia and the TNR polymorphisms within the KLHL1AS/SCA8, PPP2R2B/SCA12, and TBP/SCA17 genes. We studied 100 unrelated schizophrenia patients and 124 controls without evident neurodegenerative or psychiatric disorders. The overall allele frequency distributions of the KLHL1AS/SCA8 and PPP2R2B/SCA12 genes were not significantly different between the schizophrenic patients and the control subjects (P>0.05). The allele frequency distribution in the schizophrenic patients was significantly different from that in the controls at the TBP/SCA17 gene (P=0.0149), with an increased frequency of 36 repeats in the patients and two patients carrying 45 TNR expansions were identified. TBP/SCA17 is the TATA box binding protein gene mapped to chromosome 6q27. The study suggests that TNR expansions of the TBP/SCA17 gene may contribute to the genetic risk of schizophrenia in rare cases.
Asunto(s)
Cromosomas Humanos Par 6/genética , Esquizofrenia/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Expansión de Repetición de Trinucleótido/genética , Adulto , Pueblo Asiatico/genética , Mapeo Cromosómico , Femenino , Humanos , Masculino , Proteínas del Tejido Nervioso/genética , Fosfoproteínas Fosfatasas/genética , Reacción en Cadena de la Polimerasa , Polimorfismo Genético/genética , Proteína Fosfatasa 2 , ARN Largo no Codificante , ARN no TraducidoRESUMEN
BACKGROUND: Miyoshi distal myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B) were found to map to the same mutant gene encoding for dysferlin on chromosome 2p13. Most reported cases were large inbred kindreds whose members demonstrated both MM and LGMD2B phenotypes. OBJECTIVE: To investigate the clinical, neurophysiological, histopathological, and genetic features in 4 patients with MM from 2 unrelated Chinese families demonstrating linkage to the dysferlin locus. RESULTS: All patients were characterized by early adult onset, preferential atrophy, and weakness of calf muscles, marked elevation of serum creatine kinase levels, and absence of dysferlin staining. Magnetic resonance imaging showed fatty and fibrotic tissue signals in the affected muscles. Genetic analysis revealed novel compound heterozygous mutations, 1310+1G to A and GGG to GTC transition at nucleotide 1650 (G426V ) in one family and another novel compound heterozygous mutation, a deletion of C at nucleotide 477 and a CCG to CTG transition at nucleotide 6576 (P2068L), in the other family. CONCLUSION: Miyoshi distal myopathy in these 2 Chinese families demonstrated a homogenous phenotype and compound heterozygous mutations. Among the 4 mutations, 3 were novel mutations that, to our knowledge, have not been reported previously.
