SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations
SPG35 contributes to the second common subtype of AR-HSP in China: frequency analysis and functional characterization of FA2H gene mutations
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SPG35促成中国AR-HSP第二种常见亚型：FA2H基因突变的频率分析和功能表征
DOI：
10.1111/cge.12336
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发表时间：
2015-01-01
影响因子：
3.5
通讯作者：
Shen, L.
中科院分区：
文献类型：
--
作者：
Liao, X.;Luo, Y.;Shen, L.
遗传性痉挛截瘫(HSPs)是一组临床和遗传上不同类型的神经退行性疾病。最近，脂肪酸2-羟基酶基因(FA2H)突变被发现与35型热休克蛋白(SPG35)有关。本研究旨在明确FA2H基因在中国人常染色体隐性遗传性过敏性紫杉醇(AR-HSP)患者中的作用，并为了解这些新突变的酶功能提供依据。对31个AR-HSP家系和55例无SPG11、SPG15、SPG5和SPG7基因突变的散发性病例进行FA2H直接测序。进一步检测突变蛋白的酶活性。在两个中国人家系中发现了三个新的突变，包括两个复合杂合突变(c.388C>；T/p.L130F和c.506+6C>；G)和一个纯合子突变(c.230T>；G/p.L77R)。C.506+6C>；G剪接点突变导致外显子3缺失。酶功能测定显示，与p.L130F和p.L77R相关的FA2H的酶活性显著降低。总体而言，我们的数据拓宽了FA2H上突变的谱，功能分析表明这些突变严重损害了FA2H的酶活性。此外，频率分析显示，SPG35是中国AR-HSP的第二常见亚型。
Hereditary spastic paraplegias (HSPs) encompass a clinically and genetically heterogeneous group of neurodegenerative disorders. Recently, mutations in fatty acid 2-hydroxylase gene (FA2H) have been identified responsible for HSPs type 35 (SPG35). This study aims to define the contribution of FA2H to Chinese autosomal recessive HSP (AR-HSP) patients and provide insights into the enzymatic functions of the novel mutations. Direct sequencing of FA2H was conducted in 31 AR-HSP families and 55 sporadic cases without SPG11, SPG15, SPG5 and SPG7 gene mutations. Enzymatic activity of the mutated proteins was further examined. Three novel mutations were found in two Chinese families, including two compound heterozygous mutations (c.388C>T/p.L130F and c.506+6C>G) and one homozygous mutation (c.230T>G/p.L77R). The c.506+6C>G splice-site mutation led to the deletion of exon 3. Measurement of enzymatic functions revealed a significant reduction in the enzymatic activity of FA2H associated with p.L130F and p.L77R. Overall, our data widens the spectrum of the mutations on FA2H, and functional analyses indicate that these mutations severely impair the enzymatic activity of FA2H. Furthermore, frequency analysis shows that SPG35 is the second most common subtype of AR-HSP in China.