Trinucleotide repeats in 202 families with ataxia -: A small expanded (CAG)n allele at the SCA17 locus
Trinucleotide repeats in 202 families with ataxia -: A small expanded (CAG)n allele at the SCA17 locus
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DOI：
10.1001/archneur.59.4.623
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发表时间：
2002-04-01
影响因子：
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通讯作者：
Sequeiros, J
中科院分区：
文献类型：
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作者：
Silveira, I;Miranda, C;Sequeiros, J
背景资料：已知十种以脊髓小脑共济失调（SCA）为特征的神经退行性疾病由三核苷酸重复序列（TNR）扩增引起。然而，在某些情况下，分子诊断被认为是不确定的，因为正常和受影响的等位基因范围之间的重叠。目的：研究一组葡萄牙和巴西共济失调家系的临床和分子特征，以提高对SCA分子诊断的认识。（3）研究了202例葡萄牙和巴西SCA患者的基因型-表型相关性。结果：110个SCA家系的患者在其中1个位点出现TNR扩增。显性传播病例在Machado-Joseph病基因（MJD 1）（63%）、SCA 2（3%）、齿状核红核苍白球路易体萎缩基因（DRPLA）（2%）、SCA 6（1%）或SCA 7（1%）位点有（CAG）（n）扩增，或在SCA 8（2%）基因有（CTG）（n）扩增，而Freidreich共济失调基因（FRDA）的（GAA）（n）扩增在64%的隐性共济失调家族中被发现。孤立的患者在MJD 1（6%），SCA 8（6%）或FRDA（8%）基因上也有TNR扩增;此外，TATA结合蛋白基因（TBP）的扩增等位基因，43个CAG，存在于共济失调和精神恶化的患者中。SCA 2和SCA 6的频率和频率的大正常等位基因之间的关联被发现在葡萄牙和巴西的个人，分别。有趣的是，DRPLA和大的正常等位基因的频率之间没有关联被发现在Portuguese group.Conclusions：我们的研究结果表明，（1）一个显着的孤立的共济失调病例是由于TNR扩张;（2）扩大DRPLA等位基因在葡萄牙家庭可能已经从祖先的单倍型进化;和（3）小（CAG），在TBP基因的扩张可能会导致SCA 17。
Background: Ten neurodegenerative disorders characterized by spinocerebellar ataxia (SCA) are known to be caused by trinucleotide repeat (TNR) expansions. However, in some instances the molecular diagnosis is considered indeterminate because of the overlap between normal and affected allele ranges. In addition, the mechanism that generates expanded alleles is not completely understood.Objective: To examine the clinical and molecular characteristics of a large group of Portuguese and Brazilian families with ataxia to improve knowledge of the molecular diagnosis of SCA.Patients and Methods: We have (1) assessed repeat sizes at all known TNR loci implicated in SCA; (2) determined frequency distributions of normal alleles and expansions; and (3) looked at genotype-phenotype correlations in 202 unrelated Portuguese and Brazilian patients with SCA. Molecular analysis of TNR expansions was performed using polymerase chain reaction amplification.Results: Patients from 110 unrelated families with SCA showed TNR expansions at 1 of the loci studied. Dominantly transmitted cases had (CAG)(n) expansions at the Machado-Joseph disease gene (MJD1) (63%), at SCA2 (3%), the gene for dentatorubropallidoluysian atrophy (DRPLA) (2%), SCA6 (1%), or SCA7 (1%) loci, or (CTG)(n) expansions at the SCA8 (2%) gene, whereas (GAA)(n) expansions in the Freidreich ataxia gene (FRDA) were found in 64% of families with recessive ataxia. Isolated patients also had TNR expansions at the MJD1 (6%), SCA8 (6%), or FRDA (8%) genes; in addition, an expanded allele at the TATA-binding protein gene (TBP), with 43 CAGs, was present in a patient with ataxia and mental deterioration. Associations between frequencies of SCA2 and SCA6 and a frequency of large normal alleles were found in Portuguese and Brazilian individuals, respectively. Interestingly, no association between the frequencies of DRPLA and large normal alleles was found in the Portuguese group.Conclusions: Our results show that (1) a significant number of isolated cases of ataxia are due to TNR expansions; (2) expanded DRPLA alleles in Portuguese families may have evolved from an ancestral haplotype; and (3) small (CAG), expansions at the TBP gene may cause SCA17.