RESUMEN
Parkinson's disease (PD) is a common neurodegenerative disorder with clinical features of bradykinesia, rigidity and resting tremor resulting from the deficiency of dopamine in the nigrostriatal system. Previously we mapped a susceptibility gene for an autosomal dominant form of PD to a 10.6 cM region of chromosome 2p (PARK3; OMIM 602404). Here we report the identification and characterization of the human sideroflexin 5 gene (SFXN5), which maps to the critical PARK3 region. Database analysis and 5'-RACE (rapid amplification of cDNA ends) identified a 4191 bp cDNA, encoding a predicted protein of 340 amino acids. The genomic sequence and structure of SFXN5 confirmed the cDNA sequence. Northern blot analysis revealed a single SFXN5 transcript of approximately 4.3 kb, which was primarily expressed in the brain. An examination of SFXN5 expression in specific regions of the human brain revealed high levels of expression in all regions analyzed. Sequence analysis of 2p13 linked individuals affected with PD did not reveal any potentially pathogenic mutations within SFXN5, suggesting SFXN5 does not correspond to PARK3.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Proteínas del Tejido Nervioso/genética , Enfermedad de Parkinson/genética , Secuencia de Aminoácidos , Secuencia de Bases , Mapeo Cromosómico , Cromosomas Humanos Par 2/genética , ADN Complementario/química , ADN Complementario/genética , ADN Complementario/aislamiento & purificación , Exones , Salud de la Familia , Femenino , Expresión Génica , Genes/genética , Humanos , Intrones , Masculino , Datos de Secuencia Molecular , Alineación de Secuencia , Análisis de Secuencia de ADN , Homología de Secuencia de AminoácidoRESUMEN
PURPOSE: We describe two newly discovered large Polish families with Parkinsonism, PL-Krakow 1 and PL-Krakow 2. SCOPE: As illustrated by case reports from two patients, the disease phenotype is similar to that seen in patients with idiopathic Parkinson's disease, and affected individuals show a positive response to levodopa therapy. Molecular genetic studies failed to demonstrate a single chromosomal haplotype that segregated with disease for any of the known loci for Parkinsonism. CONCLUSIONS: The study of large kindreds such as this provides opportunities to find new Parkinsonian loci and mutations. This knowledge will help to better our understanding of the basic mechanisms leading to the degeneration of vulnerable substantia nigra neurons and other susceptible brain structures.
Asunto(s)
Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Trastornos Parkinsonianos/tratamiento farmacológico , Trastornos Parkinsonianos/genética , Actividades Cotidianas , Adulto , Edad de Inicio , Anciano , Demencia/etiología , Progresión de la Enfermedad , Femenino , Ligamiento Genético , Humanos , Masculino , Persona de Mediana Edad , Biología Molecular , Trastornos Parkinsonianos/complicaciones , Linaje , Fenotipo , Polonia , Incontinencia Urinaria/etiologíaRESUMEN
Spinocerebellar ataxia, type 2 (SCA2), results from an expansion of a stretch of polyglutamine repeats within the coding sequence of the ataxin-2 gene (ATX2), localized to chromosome 12q23-24. Recent studies have widened the clinical phenotype, notably for individuals with repeats of intermediate size, from 32 to 35 glutamine residues. This narrow range necessitates precise determination of repeat size. Diagnostic laboratories most often perform direct genotyping of ATX2 from polymerase chain-amplified patient DNA with subsequent sizing utilizing slab gel polyacrylamide gel electrophoresis (PAGE) or capillary electrophoresis. Using cloning and sequencing methods, we have constructed a ladder of ATX2 alleles of known size and sequence composition. This freely available size ladder will facilitate future quantification of expansions of the ATX2 locus.
Asunto(s)
Péptidos/genética , Proteínas/genética , Ataxias Espinocerebelosas/genética , Expansión de Repetición de Trinucleótido , Ataxinas , Análisis Mutacional de ADN/métodos , Proteínas del Tejido Nervioso , Reacción en Cadena de la PolimerasaRESUMEN
Parkinson's disease (PD) is a common neurodegenerative disorder with clinical features of bradykinesia, rigidity and resting tremor resulting from the deficiency of dopamine in the nigrostriatal system. Recently, PARK6 was identified as a novel locus associated with autosomal recessive PD. Here we report the identification and characterization of a novel human deubiquitylating gene (USP31), which maps to the critical PARK6 region. Database analysis and 5' RACE identified a 4070bp cDNA, encoded by 27 exons spanning approximately 105kbp of genomic sequence. The predicted protein of 1035 amino acids included a conserved ubiquitin hydrolase region (Prosite profile PS50235), a DUSP (domain in ubiquitin specific proteases-Smart00695) and a ubiquitin-like domain (Prosite pattern PS00299). Northern blot analysis revealed a single USP31 transcript of approximately 4 kb, which was primarily expressed in the testis and lung.
Asunto(s)
Endopeptidasas/genética , Regulación de la Expresión Génica/genética , Secuencia de Aminoácidos , Animales , Proteínas de Arabidopsis/química , Proteínas de Arabidopsis/genética , Emparejamiento Base , Secuencia de Bases , Secuencia Conservada , Cartilla de ADN , ADN Complementario/química , Endopeptidasas/química , Endopeptidasas/metabolismo , Genes Recesivos , Humanos , Pulmón/enzimología , Masculino , Ratones , Datos de Secuencia Molecular , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Testículo/enzimología , Temblor/genética , Ubiquitina Tiolesterasa , Proteasas Ubiquitina-EspecíficasRESUMEN
We describe several families of African origin with SCA3/Machado-Joseph disease gene expansions. In these cases, the phenotype ranges from ataxia with parkinsonian signs to a syndrome clinically almost indistinguishable from idiopathic, L-dopa-responsive Parkinson's disease. In contrast, these parkinsonian phenotypes are rare in those of European descent. Haplotype analysis shows that these African families do not share a common founder, thus a cis-acting element in the promoter is unlikely to be responsible these unusual presentations. We suggest that trans-acting factors are responsible for the variable phenotype and discuss the implications of diseases showing racially different expressivities.
Asunto(s)
Etnicidad/estadística & datos numéricos , Expresión Génica/genética , Enfermedad de Machado-Joseph/epidemiología , Enfermedad de Machado-Joseph/genética , Negro o Afroamericano/estadística & datos numéricos , Edad de Inicio , Marcadores Genéticos , Humanos , Fenotipo , Repeticiones de Trinucleótidos/genética , Población Blanca/estadística & datos numéricosRESUMEN
Some kindreds with familial parkinsonism exhibit genetic anticipation, suggesting possible involvement of trinucleotide repeat expansion. Recent reports have shown trinucleotide repeat expansions in the spinocerebellar ataxia 2 (SCA2) gene in patients with levodopa-responsive parkinsonism. We tested 136 unrelated patients with familial parkinsonism for SCA2 mutations. Two probands had borderline mutations; the rest were normal. (
Asunto(s)
Antiparkinsonianos/uso terapéutico , Levodopa/uso terapéutico , Enfermedad de Parkinson/genética , Trastornos Parkinsonianos/genética , Proteínas/genética , Adulto , Anciano , Alelos , Anticipación Genética/genética , Antiparkinsonianos/efectos adversos , Ataxinas , Análisis Mutacional de ADN , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Levodopa/efectos adversos , Masculino , Persona de Mediana Edad , Proteínas del Tejido Nervioso , Examen Neurológico , Enfermedad de Parkinson/diagnóstico , Enfermedad de Parkinson/tratamiento farmacológico , Trastornos Parkinsonianos/diagnóstico , Trastornos Parkinsonianos/tratamiento farmacológico , Linaje , Fenotipo , Resultado del Tratamiento , Repeticiones de TrinucleótidosRESUMEN
We report on clinical (18)F-labeled 6-fluorodopa ((18)F-dopa) positron emission tomography (PET) and molecular genetic analyses of an ethnic Chinese family in which three siblings presented with early-onset Parkinson's disease. As described in some parkin patients, neither sleep benefit nor diurnal fluctuation was noted. Interestingly, depression, anxiety, and obsessive-compulsive disorders were manifest. The (18)F-dopa PET scans showed bilateral presynaptic dopaminergic dysfunction without marked lateralization. Molecular genetic analysis showed identical chromosome 6 haplotypes inherited by affected subjects, with alternate allelic deletions of parkin exons 3 and 4. Furthermore, mRNA analyses identified aberrantly spliced parkin transcripts, suggesting that unusual parkin protein isoforms may be expressed in the brain and retain some function.