Institute of Neurogenetics, University of Lübeck, Lübeck, Germany.
Department of Neurosciences, College of Medicine-Philippine General Hospital, University of the Philippines, Manila, Philippines.
Ann Neurol. 2019 Jun;85(6):812-822. doi: 10.1002/ana.25488. Epub 2019 May 3.
X-linked dystonia parkinsonism (XDP) is a neurodegenerative movement disorder caused by a single mutation: SINE-VNTR-Alu (SVA) retrotransposon insertion in TAF1. Recently, a (CCCTCT) repeat within the SVA insertion has been reported as an age-at-onset (AAO) modifier in XDP. Here we investigate the role of this hexanucleotide repeat in modifying expressivity of XDP.
We genotyped the hexanucleotide repeat in 355 XDP patients and correlated the repeat number (RN) with AAO (n = 295), initial clinical manifestation (n = 294), site of dystonia onset (n = 238), disease severity (n = 28), and cognitive function (n = 15). Furthermore, we investigated i) repeat instability by segregation analysis and Southern blotting using postmortem brain samples from two affected individuals and ii) relative TAF1 expression in blood RNA from 31 XDP patients.
RN showed significant inverse correlations with AAO and with TAF1 expression and a positive correlation with disease severity and cognitive dysfunction. Importantly, AAO (and not RN) was directly associated with whether dystonia or parkinsonism will manifest at onset. RN was lower in patients affected by mouth/tongue dystonia compared with blepharospasm. RN was unstable across germline transmissions with an overall tendency to increase in length and exhibited somatic mosaicism in brain.
The hexanucleotide repeat within the SVA insertion acts as a genetic modifier of disease expressivity in XDP. RN-dependent TAF1 repression and subsequent differences in TAF1 mRNA levels in patients may be potentiated in the brain through somatic variability leading to the neurological phenotype. ANN NEUROL 2019;85:812-822.
X 连锁肌张力障碍帕金森病（XDP）是一种神经退行性运动障碍，由单个突变引起：SINE-VNTR-Alu（SVA）反转录转座子插入 TAF1。最近，报道 SVA 插入内的（CCCTCT）重复序列是 XDP 的发病年龄（AAO）修饰因子。在此，我们研究了该六核苷酸重复序列在修饰 XDP 表达中的作用。
我们对 355 例 XDP 患者的六核苷酸重复序列进行了基因分型，并将重复数（RN）与 AAO（n=295）、初始临床表现（n=294）、肌张力障碍起始部位（n=238）、疾病严重程度（n=28）和认知功能（n=15）相关联。此外，我们通过对两个受影响个体的死后脑组织样本进行分离分析和 Southern 印迹研究，调查了 i）重复不稳定性，以及通过 31 例 XDP 患者的血液 RNA 调查了 ii）相对 TAF1 表达。
RN 与 AAO 和 TAF1 表达呈显著负相关，与疾病严重程度和认知功能障碍呈正相关。重要的是，AAO（而非 RN）与发病时是否出现肌张力障碍或帕金森病直接相关。与眼睑痉挛相比，口/舌肌张力障碍患者的 RN 较低。RN 在种系传播中不稳定，总体上有延长的趋势，并在脑中表现出体细胞镶嵌现象。
SVA 插入内的六核苷酸重复序列是 XDP 疾病表现的遗传修饰因子。RN 依赖性 TAF1 抑制以及患者中 TAF1 mRNA 水平的差异可能通过导致神经表型的大脑中的体细胞变异性而增强。ANN NEUROL 2019;85:812-822。
