Extended phenotypic spectrum of KIF5A mutations
Extended phenotypic spectrum of KIF5A mutations
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DOI：
10.1212/wnl.0000000000000691
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发表时间：
2014-08-12
期刊：
影响因子：
9.9
通讯作者：
Houlden, Henry
中科院分区：
文献类型：
--
作者：
Liu, Yo-Tsen;Laura, Matilde;Houlden, Henry
目的：建立KIF 5A基因突变的表型谱，探讨KIF 5A基因突变是否导致与遗传性痉挛性截瘫（HSP）或典型腓骨肌萎缩症2型（CMT 2）相关的轴突神经病变。方法：对186例临床诊断为HSP和215例典型CMT 2患者的运动域编码外显子进行KIF 5A基因测序。对66例伴有锥体束征的HSP或CMT 2患者进行KIF 5A基因的全外显子测序。结果：在6例无关患者中发现5种KIF 5A突变：R204 W和D232 N为新突变; R204 Q、R280 C和R280 H为已有报道。3例患者以CMT 2为主要表现型，其中2例还出现锥体束征。其他3例患者表现为HSP，但也有显着的轴突神经病变或其他额外的feature.Conclusion：这是目前最大的研究调查KIF 5A突变。通过结合下一代测序和常规测序，我们证实KIF 5A突变可以导致从HSP到CMT 2的可变表型。CMT 2突变的鉴定拓宽了表型谱，并强调了KIF 5A突变的重要性，KIF 5A突变涉及中枢和外周神经系统的变性，应在HSP和CMT 2中进行测试。
Objective: To establish the phenotypic spectrum of KIF5A mutations and to investigate whether KIF5A mutations cause axonal neuropathy associated with hereditary spastic paraplegia (HSP) or typical Charcot-Marie-Tooth disease type 2 (CMT2).Methods: KIF5A sequencing of the motor-domain coding exons was performed in 186 patients with the clinical diagnosis of HSP and in 215 patients with typical CMT2. Another 66 patients with HSP or CMT2 with pyramidal signs were sequenced for all exons of KIF5A by targeted resequencing. One additional patient was genetically diagnosed by whole-exome sequencing.Results: Five KIF5A mutations were identified in 6 unrelated patients: R204W and D232N were novel mutations; R204Q, R280C, and R280H have been previously reported. Three patients had CMT2 as the predominant and presenting phenotype; 2 of them also had pyramidal signs. The other 3 patients presented with HSP but also had significant axonal neuropathy or other additional features.Conclusion: This is currently the largest study investigating KIF5A mutations. By combining next-generation sequencing and conventional sequencing, we confirm that KIF5A mutations can cause variable phenotypes ranging from HSP to CMT2. The identification of mutations in CMT2 broadens the phenotypic spectrum and underlines the importance of KIF5A mutations, which involve degeneration of both the central and peripheral nervous systems and should be tested in HSP and CMT2.