The role of mutations in COL6A3 in isolated dystonia
The role of mutations in COL6A3 in isolated dystonia
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DOI：
10.1007/s00415-016-8046-y
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发表时间：
2016-04-01
影响因子：
6
通讯作者：
Klein, Christine
中科院分区：
文献类型：
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作者：
Lohmann, Katja;Schlicht, Felix;Klein, Christine
COL6A3的特异性突变最近被报道为孤立性隐性肌张力障碍的原因，这是一种罕见的运动障碍。在所有患者中，至少有一个突变位于外显子41和42。为了尝试重复这些发现，我们通过直接测序评估了955例患有单纯性或合并性肌张力障碍或其他运动障碍伴有肌张力障碍的患者COL6A3外显子41和42的罕见变异频率。我们鉴定了9个罕见变异的杂合载体，包括5个不同的错义突变和一个极其罕见的同义变异。在这9例患者中，我们对COL6A3的其余41个编码外显子进行了测序，以检测复合杂合状态下的第二个突变。仅在其中一个中，鉴定出第二种罕见变体（Thr732Met + Pro3082Arg）。值得注意的是，由于PINK1纯合子突变，该患者被诊断为帕金森病（伴张力异常姿势）。COL6A3突变在该家族的四个患病兄弟姐妹中显然没有与疾病分离。此外，没有迹象表明COL6A3突变具有疾病修饰作用，因为疾病严重程度或发病年龄与该家庭中COL6A3突变等位基因的数量无关。结合公开数据库中报道的突变纯合携带者的相对高频率，我们的数据表明COL6A3变异在孤立性肌张力障碍中的因果作用值得商榷。
Specific mutations in COL6A3 have recently been reported as the cause of isolated recessive dystonia, which is a rare movement disorder. In all patients, at least one mutation was located in Exons 41 and 42. In an attempt to replicate these findings, we assessed by direct sequencing the frequency of rare variants in Exons 41 and 42 of COL6A3 in 955 patients with isolated or combined dystonia or with another movement disorder with dystonic features. We identified nine heterozygous carriers of rare variants including five different missense mutations and an extremely rare synonymous variant. In these nine patients, we sequenced the remaining 41 coding exons of COL6A3 to test for a second mutation in the compound heterozygous state. In only one of them, a second rare variant was identified (Thr732Met + Pro3082Arg). Of note, this patient had been diagnosed with ParkinsonA ' s disease (with dystonic posturing) due to homozygous PINK1 mutations. The COL6A3 mutations clearly did not segregate with the disease in the four affected siblings of this family. Further, there was no indication for a disease-modifying effect of the COL6A3 mutations since disease severity or age at onset did not correlate with the number of COL6A3 mutated alleles in this family. In conjunction with the relatively high frequency of homozygous carriers of reported mutations in publically available databases, our data call a causal role for variants in COL6A3 in isolated dystonia into question.