Molecular genetics of hereditary spinocerebellar ataxia - Mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families
Molecular genetics of hereditary spinocerebellar ataxia - Mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families
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DOI：
10.1001/archneur.61.5.727
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发表时间：
2004-05-01
影响因子：
--
通讯作者：
Taroni, F
中科院分区：
文献类型：
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作者：
Brusco, A;Gellera, C;Taroni, F
背景资料：常染色体显性遗传性小脑共济失调是一组临床和遗传异质性的进行性神经退行性疾病，目前与22个位点（脊髓小脑共济失调[SCA] 1-SCA 8、SCA 10-SCA 19、SCA 21、SCA 22、成纤维细胞生长因子14 [FGF 14]-SCA和齿状核红核-苍白球路易体萎缩[DRPLA]）相关。在12例病例中确定了相关基因（SCA 1 -3、SCA 6 -8、SCA 10、SCA 12、SCA 14、SCA 17、FGF 14和DRPLA），除了最近鉴定的PRKCG和FGF 14基因外，所有基因的缺陷都是由短核苷酸重复序列的扩增组成。研究意大利遗传性共济失调家族中SCA 1 -3、SCA 6 -8、SCA 10、SCA 12和SCA 17基因扩增的相对患病率，特别是验证SCA 10、SCA 12和SCA 17在意大利的发生率;通过重复扩增检测技术分析在初筛时检测结果为阴性的先证者的样本，以确定新位点的CAG/CTG扩增。患者：225例无血缘关系的意大利指数遗传性共济失调病例，其中大部分（n = 183）表现为明显的显性遗传特征。我们发现SCA 1和SCA 2基因突变占大多数病例（分别为21%和24%）。我们发现SCA 3、SCA 6、SCA 7、SCA 8和SCA 17非常罕见（各约1%），未发现SCA 10或SCA 12病例。一半的指示病例（113/225）在已知的SCA基因扩增中呈阴性。对其中111例进行的重复扩增检测分析显示，22例（20%）的CAG/CTG重复扩增至少为50个三联体。22个扩增片段中有21个可归因于2个多态位点的长度变异（扩增重复结构域CAG/ CTG 1 [ERDA 1]或染色体18q21.1上的CTG重复[CTG 18.1]）。结论：SCA 1 -3和SCA 6 -7基因突变在意大利的分布较为特殊。我们发现SCA 1和SCA 2基因扩增的频率相对较高;与其他欧洲国家相比，SCA 3，SCA 6和SCA 7突变罕见。未检测到SCA 10和SCA 12，仅检测到少数SCA 8（2/225）和SCA 17（2/225）家族。在已知SCA基因缺陷阴性的患者中，重复扩增检测数据强烈表明，至少在我们的人群中，新基因中的CAG/ CTG扩增应被认为是SCA表型的不太可能的原因。
Background: Autosomal dominant cerebellar ataxias are a clinical and genetically heterogeneous group of progressive neurodegenerative diseases, at present associated with 22 loci (spinocerebellar ataxia [SCA] 1-SCA8, SCA10-SCA19, SCA21, SCA22, fibroblast growth factor 14 [FGF14]-SCA, and dentatorubral-pallidoluysian atrophy [DRPLA]). The relevant gene has been identified in 12 cases (SCA1-3, SCA6-8, SCA10, SCA12, SCA14, SCA17, FGF14, and DRPLA), and in all but the recently identified PRKCG and FGF14 genes, the defect consists of the expansion of a short nucleotide repeat.Objectives: To investigate the relative prevalence of SCA1-3, SCA6-8, SCA10, SCA12, and SCA17 gene expansions in Italian families with hereditary ataxia, specifically to verify the occurrence of SCA10, SCA12, and SCA17 in Italy; and to analyze samples from probands with negative test results at the initial screening by means of the repeat expansion detection technique to identify CAG/CTG expansions in novel loci.Patients: Two hundred twenty-five unrelated Italian index cases with hereditary ataxia, most (n = 183) of whom presented with a clear dominantly transmitted trait.Results: We found that SCA1 and SCA2 gene mutations accounted for most cases (21% and 24%, respectively). We found SCA3, SCA6, SCA7, SCA8, and SCA17 to be very rare (approximately 1% each), and no case of SCA10 or SCA12 was identified. Half of the index cases (113/225) were negative for expansions in the known SCA genes. Repeat expansion detection analysis performed on 111 of these cases showed a CAG/CTG repeat expansion of at least 50 triplets in 22 (20%). Twenty-one of 22 expansions could be attributed to length variation at 2 polymorphic loci (expanded repeat domain CAG/ CTG 1 [ERDA1] or CTG repeat on chromosome 18q21.1 [CTG18.1]). In 1 patient, the expansion was assigned to the DRPLA gene.Conclusions: The distribution of SCA1-3 and SCA6-7 gene mutations is peculiar in Italy. We found a relatively high frequency of SCA1 and SCA2 gene expansions; SCA3, SCA6, and SCA7 mutations were rare, compared with other European countries. No SCA10 or SCA12 and only a few SCA8 (2/225) and SCA17 (2/225) families were detected. In patients negative for defects in known SCA genes, repeat expansion detection data strongly suggest that, at least in our population, CAG/ CTG expansions in novel genes should be considered an unlikely cause of the SCA phenotype.