Beetz Christian, Schüle Rebecca, Deconinck Tine, Tran-Viet Khanh-Nhat, Zhu Hui, Kremer Berry P H, Frints Suzanna G M, van Zelst-Stams Wendy A G, Byrne Paula, Otto Susanne, Nygren Anders O H, Baets Jonathan, Smets Katrien, Ceulemans Berten, Dan Bernard, Nagan Narasimhan, Kassubek Jan, Klimpe Sven, Klopstock Thomas, Stolze Henning, Smeets Hubert J M, Schrander-Stumpel Constance T R M, Hutchinson Michael, van de Warrenburg Bart P, Braastad Corey, Deufel Thomas, Pericak-Vance Margaret, Schöls Ludger, de Jonghe Peter, Züchner Stephan
Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Jena, Germany.
Brain. 2008 Apr;131(Pt 4):1078-86. doi: 10.1093/brain/awn026. Epub 2008 Mar 5.
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 2-7 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.
最近有报道称，受体表达增强蛋白1（REEP1）的突变可导致常染色体显性遗传性痉挛性截瘫（HSP）SPG31型。通过一项大规模合作研究，我们对535名无血缘关系的HSP患者样本进行了REEP1突变和拷贝数变异筛查。通过直接测序分析，我们在16名家族性和散发性患者中鉴定出13个新的REEP1突变和2个已知突变。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移位，随后翻译提前终止和单倍剂量不足。有趣的是，我们在REEP1的3'-UTR中鉴定出两个与疾病相关的变异，它们位于高度保守的微小RNA结合位点。对133名HSP索引患者的一个子集进行的拷贝数变异分析显示，在一个爱尔兰家族中，REEP1存在一个涉及外显子2 - 7的大片段重复。临床上，大多数SPG31患者表现为单纯性痉挛性截瘫；罕见的复杂特征仅限于周围神经受累的症状或体征。有趣的是，发病年龄分布呈现双峰模式，疾病初始症状出现在20岁之前或30岁之后。在我们临床异质性样本中的总体突变率为3.0%；然而，在单纯HSP子样本中，REEP1突变占所有患者的8.2%。这些结果明确将REEP1确立为一个相对常见的常染色体显性HSP基因，对此进行基因检测是必要的。我们还确定单倍剂量不足是SPG31的主要分子遗传机制，这应该启动并指导对REEP1的功能研究，重点是功能丧失机制。我们的结果应可作为REEP1突变频率、突变谱以及与SPG31相关的临床表型的有效参考。
