Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability
Spastic paraplegia type 4: A novel SPAST splice site donor mutation and expansion of the phenotype variability
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DOI：
10.1016/j.jns.2017.07.011
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发表时间：
2017-09-15
影响因子：
4.4
通讯作者：
Orlacchio, Antonio
中科院分区：
文献类型：
--
作者：
Kawarai, Toshitaka;Montecchiani, Celeste;Orlacchio, Antonio
SPG4/SPAST突变是常染色体显性遗传性痉挛性截瘫（HSP）最常见的分子病因。SPAST的功能丧失和单倍功能不全已被证实，单纯型痉挛性截瘫是主要临床表现。本研究旨在探讨新的SPAST剪接位点供体变异体c.1004 + 3A> C，在两个家庭，一个来自意大利和日本的7名患者。外显子6被变异体跳过，导致翻译提前终止，p.Gly290Trpfs * S。淋巴细胞中SPAS7转录物的测量表明通过无义介导的mRNA衰变（NMD）减少。观察到家族内和家族间的表型变异，包括发病年龄、痉挛的严重程度和脊柱侧凸。我们的研究进一步证明了SPG4的等位基因异质性，NMD的剂量效应以及SPAST突变的广泛临床特征。(C)2017爱思唯尔B.V.保留所有权利。
Mutations in SPG4/SPAST are the most frequent molecular aetiology in the autosomal dominant form of hereditary spastic paraplegia (HSP). Loss-of-function and haploinsufficiency in SPAST have been demonstrated and the pure form of spastic paraplegia is a main clinical manifestation. This study is to explore the novel SPAST splice site donor variant, c.1004 + 3A> C, in seven patients from two families, one from Italy and the other from Japan. Exon 6 is skipped out by the variant, leading to a premature termination of translation, p.Gly290Trpfs*S. Measurement of SPAS7 transcripts in lymphocytes demonstrated a reduction through nonsense-mediated mRNA decay (NMD). Intra- and inter-familial phenotypic variations were observed, including age-at-onset, severity of spasticity, and scoliosis. Our study demonstrated further evidence of allelic heterogeneity in SPG4, dosage effects through NMD, and broad clinical features of the SPAST mutation. (C) 2017 Elsevier B.V. All rights reserved.