A NOVEL CAG REPEAT CONFIGURATION IN THE SCA1 GENE - IMPLICATIONS FOR THE MOLECULAR DIAGNOSTICS OF SPINOCEREBELLAR ATAXIA TYPE-1
A NOVEL CAG REPEAT CONFIGURATION IN THE SCA1 GENE - IMPLICATIONS FOR THE MOLECULAR DIAGNOSTICS OF SPINOCEREBELLAR ATAXIA TYPE-1
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DOI：
10.1093/hmg/4.12.2411
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发表时间：
1995-12-01
影响因子：
3.5
通讯作者：
POPOVICH, BW
中科院分区：
文献类型：
--
作者：
QUAN, F;JANAS, J;POPOVICH, BW
脊髓小脑共济失调1型（SCA 1）是一种常染色体显性遗传的神经退行性疾病，其特征为小脑、脑干和脊髓小脑束神经元的进行性丢失（1，2）。患者通常表现为共济失调、构音障碍和延髓表现，与颅神经IX、X和XII功能障碍一致（3，4）。症状通常在第三和第四个十年之间出现，10-20年后因延髓功能障碍而死亡。在某些运动病中也可观察到青少年发病（18岁或以下）（5，6）。SCA 1基因定位于染色体6p 22 -23（7，8）。SCA 1是由SCA 1基因编码区多态性CAG重复扩增引起的（9，10）。正常SCA 1等位基因携带19-36个重复，而突变等位基因携带41-81个重复，在青少年发病病例中发现了更大的重复（11，12）。正常等位基因携带被具有1-3个CAT三核苷酸的单个区域中断的CAG重复序列，而扩增的等位基因携带不间断的重复序列（12）。我们现在描述一个正常的SCA 1等位基因与扩大，但新的CAG重复配置。这个独特的等位基因的特征表明，SCA 1的分子诊断不能仅仅基于重复序列的大小，并表明疾病等位基因的分子决定因素可能是最长的不间断CAG重复序列的长度，而不是总的重复序列大小。先证者（II-1）是一名6岁2个月的女性，有轻度发育迟缓，躯干共济失调始于2岁，头部蹒跚和扫描语言，没有构音障碍或眼球震颤的迹象。颅神经功能几乎完好无损。然而，反射的缺乏和神经传导速度降低的发现与周围神经病变一致。对先证者父母的检查未能发现神经损伤的迹象。无其他神经系统疾病家族史。为了排除先证者中青少年发作的SCA 1的诊断，使用引物Rep-1和Rep-2通过PCR扩增SCA 1 CAG重复序列，其位于重复序列的侧翼（9）。该分析表明先证者携带具有28个CAG重复的正常等位基因和具有44个CAG重复的扩增等位基因（图2，泳道1）。SCA 1等位基因重复数大于36显然与SCA 1的诊断一致（11），但与先证者早期症状发作不一致。在青少年发作的SCA 1中，CAG重复扩增的大小通常在受影响大小范围的上限（9，11）。例如，在一名发病年龄为4岁的患者中报告了具有81个CAG重复的等位基因
Spinocerebellar ataxia type 1 (SCA1) is an autosomal dominant, neurodegenerative disorder characterized by the progressive loss of neurons from the cerebellum, brain stem and spinocerebellar tracts (1, 2). Patients typically manifest with ataxia, dysarthria and bulbar findings consistent with the dysfunction of cranial nerves IX, X and XII (3, 4). Symptoms usually manifest between the third and fourth decade with death resulting from bulbar dysfunction after 10-20 years. Juvenileonset (age 18 years or less) has also been seen in some kindreds (5, 6). The gene for SCA1 has been mapped to chromosome 6p22-23 (7, 8). SCA1 is caused by the expansion of a polymorphic CAG repeat in the coding region of the SCA1 gene (9, 10). Normal SCA1 alleles carry 19-36 repeats while mutant alleles carry 41-81 repeats, with larger repeats found in juvenile-onset cases (11, 12). Normal alleles carry CAG repeats interrupted by a single region with 1-3 CAT trinucleotides while expanded alleles carry uninterrupted repeats (12). We now describe a normal SCA1 allele with an expanded but novel CAG repeat configuration. The characterization of this unique allele demonstrates that a molecular diagnosis of SCA1 cannot be made solely on the basis of repeat size and indicates that the molecular determinant of a disease allele may be the length of the longest uninterrupted CAG repeat rather than total repeat size.The pedigree of the investigated family is shown in Figure 1. The proband (II-1) was a 6 year 2 month old female with mild developmental delay, truncal ataxia initiating at age 2 years, head titubation and scanning speech, with no indication of dysarthria or nystagmus. Cranial nerve function was virtually intact. However, the absence of reflexes and the finding of decreased nerve conduction velocities were consistent with a peripheral neuropathy. Examination of the proband's parents failed to reveal signs of neurological impairment. There was no other family history of neurological disorders. To rule out a diagnosis of juvenile-onset SCA1 in the proband, the SCA1 CAG repeat was amplified by PCR using the primers Rep-1 and Rep-2, flanking the repeat (9). This analysis demonstrated that the proband carried a normal allele with 28 CAG repeats and an expanded allele with 44 CAG repeats (Fig. 2, lane 1). The presence of an SCA1 allele with greater than 36 repeats was clearly consistent with a diagnosis of SCA1 (11) but inconsistent with the proband's early onset of symptoms. In juvenile-onset SCA1, the size of the CAG repeat expansion is typically in the upper end of the affected size range (9, 11). For example, an allele with 81 CAG repeats has been reported in a patient with an age-of-onset of 4 years