REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31
REEP1 mutation spectrum and genotype/phenotype correlation in hereditary spastic paraplegia type 31
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DOI：
10.1093/brain/awn026
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发表时间：
2008-04-01
期刊：
影响因子：
14.5
通讯作者：
Zuechner, Stephan
中科院分区：
文献类型：
--
作者：
Beetz, Christian;Schuele, Rebecca;Zuechner, Stephan
受体表达增强蛋白1（REEP 1）的突变最近被报道引起常染色体显性遗传性痉挛性截瘫（HSP）SPG 31型。在一次大型的合作努力中，我们筛选了535名不相关的HSP患者的REEP 1突变和拷贝数变异样本。我们通过直接测序分析在16例家族性和散发性患者中发现了13个新的和2个已知的REEP 1突变。16个突变中有12个是小插入、缺失或剪接位点突变。这些变化将导致开放阅读框的移动，随后是翻译的过早终止和单倍不足。有趣的是，我们在REEP 1的3-UTR中鉴定了两个疾病相关的变异，它们落入高度保守的microRNA结合位点。在一个子集的133 HSP指数患者的拷贝数变异分析发现一个大的重复REEP 1，涉及外显子27在爱尔兰家庭。临床上大多数SPG 31患者表现为单纯痉挛性截瘫;罕见的并发症仅限于周围神经受累的症状或体征。有趣的是，发病年龄的分布表明，一个双峰模式与疾病的初始症状的外观之前的20岁或30岁之后。我们的临床异质性样本的总体突变率为3.0;然而，在纯HSP REEP 1突变的子样本中，占所有患者的8.2。这些结果坚定地建立REEP 1作为一个相对频繁的常染色体显性HSP基因，基因检测是必要的。我们还建立了单倍不足作为SPG 31的主要分子遗传机制，这应该启动和指导REEP 1的功能研究，重点是功能丧失机制。我们的研究结果应该是有效的参考突变频率，频谱REEP 1突变，与SPG 31相关的临床表型。
Mutations in the receptor expression enhancing protein 1 (REEP1) have recently been reported to cause autosomal dominant hereditary spastic paraplegia (HSP) type SPG31. In a large collaborative effort, we screened a sample of 535 unrelated HSP patients for REEP1 mutations and copy number variations. We identified 13 novel and 2 known REEP1 mutations in 16 familial and sporadic patients by direct sequencing analysis. Twelve out of 16 mutations were small insertions, deletions or splice site mutations. These changes would result in shifts of the open-reading-frame followed by premature termination of translation and haploinsufficiency. Interestingly, we identified two disease associated variations in the 3-UTR of REEP1 that fell into highly conserved micro RNA binding sites. Copy number variation analysis in a subset of 133 HSP index patients revealed a large duplication of REEP1 that involved exons 27 in an Irish family. Clinically most SPG31 patients present with a pure spastic paraplegia; rare complicating features were restricted to symptoms or signs of peripheral nerve involvement. Interestingly, the distribution of age at onset suggested a bimodal pattern with the appearance of initial symptoms of disease either before the age of 20 years or after the age of 30 years. The overall mutation rate in our clinically heterogeneous sample was 3.0; however, in the sub-sample of pure HSP REEP1 mutations accounted for 8.2 of all patients. These results firmly establish REEP1 as a relatively frequent autosomal dominant HSP gene for which genetic testing is warranted. We also establish haploinsufficiency as the main molecular genetic mechanism in SPG31, which should initiate and guide functional studies on REEP1 with a focus on loss-of-function mechanisms. Our results should be valid as a reference for mutation frequency, spectrum of REEP1 mutations, and clinical phenotypes associated with SPG31.