Assuntos
Ataxia/genética , Síndrome do Cromossomo X Frágil/genética , Proteínas do Tecido Nervoso/genética , Proteínas de Ligação a RNA/genética , Idoso , Ataxia/fisiopatologia , Feminino , Proteína do X Frágil da Deficiência Intelectual , Síndrome do Cromossomo X Frágil/fisiopatologia , Humanos , Masculino , Repetições de Trinucleotídeos/genéticaRESUMO
An expanded polyglutamine domain in the TATA-binding protein (TBP) has been described in patients with spinocerebellar ataxia type 17 (SCA17) characterized by cerebellar ataxia associated with dementia. TBP is a general transcription initiation factor that regulates the expression of most eukaryotic genes transcribed by RNA polymerase II. SCA17, as an autosomal dominantly inherited progressive neurodegenerative disorder, is caused by heterozygous expansion of a CAG repeat coding for glutamine. Alleles with 27 to a maximum of 44 glutamine residues were found as the normal range, whereas expansions above 45 repeat units were considered pathological. Here, we present a patient with a very severe phenotype with a late onset but rapidly progressing ataxia associated with dementia and homozygous 47 glutamine residues caused by an apparent partial isodisomy 6. This extraordinary case has important implications for the insights of TBP and SCA17. The expanded polyglutamine domain in both TBP copies is not correlated with embryonic death indicating that the normal function of the protein is not disrupted by this kind of mutation but may account for the dementia seen in this patient.
Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 6 , Ataxias Espinocerebelares/genética , Fatores Associados à Proteína de Ligação a TATA/genética , Expansão das Repetições de Trinucleotídeos , Adulto , Idade de Início , Demência/complicações , Demência/genética , Feminino , Homozigoto , Humanos , Repetições de Microssatélites , Fatores de Iniciação de Peptídeos/genética , Peptídeos/genéticaRESUMO
The main mutation causing Friedreich ataxia (FRDA) is the expansion of a GAA repeat localized within the intron between exon 1 and exon 2 of the gene X25. This expansion has been observed in 98% of FRDA chromosomes. To analyze frequencies of markers tightly linked to the Friedreich ataxia gene and to investigate wheter a limited number of ancestral chromosomes are shared by German FRDA families, a detailed analysis employing nine polymorphic markers was performed. We found strong linkage disequilibria and association of FRDA expansions with a few haplotypes. FRDA haplotypes differ significantly from control haplotypes. Our results confirm that GAA repeat expansions in intron 1 of the frataxin gene are limited to a few chromosomes and indicate an obvious founder effect in German patients. Based on these analyses, we estimate a minimum age of the mutation of 107 generations.
Assuntos
Ataxia de Friedreich/genética , Proteínas de Ligação ao Ferro , Desequilíbrio de Ligação , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Evolução Molecular , Alemanha , Haplótipos , Humanos , Polimorfismo de Fragmento de Restrição , Análise de Sequência de DNA , Expansão das Repetições de Trinucleotídeos , FrataxinaRESUMO
Neurodegenerative disorders, including spin-ocerebellar ataxias (SCA), Huntington disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA), are associated with unstable CAG repeats. To investigate the mitotic stability of the repetitive element in the genes for SCA1, SCA3, HD, and DRPLA we extracted DNA from up to 13 tissue samples from four deceased individuals with progressive neurological disorders and neuropathological signs. Due to the formalin fixation of some tissues the genomic DNA was highly degraded and unsuitable for amplification of fragments longer than 150 bp. After size selection and primer extension preamplification, specific analyses could be performed even for expanded alleles. In all four patients the SCA1 mutation could be demonstrated, in one case with remarkable somatic heterogeneity of the elongated allele, whereas alleles of the normal range were stable in all tissues examined.