Charles P, Camuzat A, Benammar N, Sellal F, Destée A, Bonnet A-M, Lesage S, Le Ber I, Stevanin G, Dürr A, Brice A
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Genetics and Cytogenetics, Paris, France.
Neurology. 2007 Nov 20;69(21):1970-5. doi: 10.1212/01.wnl.0000269323.21969.db. Epub 2007 Jun 13.
Autosomal dominant parkinsonism (ADP) is caused in a large percentage of familial and sporadic cases by mutations in the LRRK2 gene, particularly G2019S. It is also caused by mutations in genes associated with autosomal dominant cerebellar ataxia (ADCA), notably CAG/CAA repeat expansions in SCA2.
We screened 164 families with ADP for expansions in the SCA2, 3, and 17 genes and for the G2019S mutation in LRRK2. The SCA2 CAG/CAA repeat expansion was sequenced to determine its structure. The phenotypes of patients with ADP caused by the SCA2, LRRK2, and unknown mutations were compared, as well as those of SCA2 patients with interrupted or uninterrupted expansions of the same size.
Three French ADP families had SCA2 mutations. The expansions ranged from 37 to 39 repeats and were interrupted and stable upon transmission. All patients (n = 9) had levodopa-responsive parkinsonism without cerebellar signs. They had significantly more symmetric signs and less rigidity than ADP caused by the G2019S mutation in LRRK2 or by unknown mutations. Interestingly, two sisters carrying both the SCA2 and the G2019S LRRK2 mutations had markedly earlier onset than their mother with only SCA2. In contrast, similar-sized but uninterrupted repeats were associated with ADCA in which cerebellar ataxia was constant and associated only rarely with one or more mild parkinsonian signs.
These results suggest that the configuration of the SCA2 CAG/CAA repeat expansions plays an important role in phenotype variability. Uninterrupted SCA2 repeat expansions found in families with autosomal dominant cerebellar ataxia result in somatic mosaicism and produce large hairpin RNAs, which may interact with double-stranded RNA-binding proteins. These characteristics are modified by interruption of the SCA2 repeat expansion as found in families with autosomal dominant parkinsonism.
在大部分家族性和散发性常染色体显性帕金森病（ADP）病例中，是由亮氨酸重复激酶2（LRRK2）基因的突变引起，尤其是G2019S突变。它也可由与常染色体显性小脑共济失调（ADCA）相关的基因突变引起，特别是脊髓小脑共济失调2型（SCA2）中的CAG/CAA重复序列扩增。
我们对164个患有ADP的家系进行筛查，检测SCA2、3和17基因的扩增以及LRRK2基因中的G2019S突变。对SCA2的CAG/CAA重复序列扩增进行测序以确定其结构。比较了由SCA2、LRRK2和未知突变引起的ADP患者的表型，以及相同大小的中断或未中断扩增的SCA2患者的表型。
三个法国家族性ADP家系存在SCA2突变。扩增范围为37至39次重复，呈中断状态且在传递过程中稳定。所有患者（n = 9）均有左旋多巴反应性帕金森病，无小脑体征。与由LRRK2基因中的G2019S突变或未知突变引起的ADP相比，他们的体征对称性明显更高，僵硬程度更低。有趣的是，两名同时携带SCA2和G2019S LRRK2突变的姐妹发病明显早于仅携带SCA2突变的母亲。相比之下，大小相似但未中断的重复序列与ADCA相关，其中小脑共济失调持续存在，仅很少与一种或多种轻度帕金森病体征相关。
这些结果表明，SCA2的CAG/CAA重复序列扩增的结构在表型变异性中起重要作用。在常染色体显性小脑共济失调家系中发现的未中断的SCA2重复序列扩增导致体细胞镶嵌现象，并产生大的发夹RNA，其可能与双链RNA结合蛋白相互作用。如在常染色体显性帕金森病家系中发现的那样，SCA2重复序列扩增的中断改变了这些特征。
