A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis
A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis
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DOI：
10.1136/jmedgenet-2012-100742
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发表时间：
2012-07-01
影响因子：
4
通讯作者：
Falik-Zaccai, Tzipora C.
中科院分区：
文献类型：
--
作者：
Zivony-Elboum, Yifat;Westbroek, Wendy;Falik-Zaccai, Tzipora C.
背景：两种看似无关的阿拉伯穆斯林起源的成员表现为明显的早发性痉挛性下肢麻痹，轻度智力残疾，后凸，胸凸和多毛。方法对患者进行神经学和发育检查。作者进行了全基因组连锁和单倍型分析，然后对候选基因进行测序；RNA和蛋白表达研究；最后对斑马鱼注射低敲氨基皂苷寡核苷酸进行了原理验证研究。结果作者描述了一种常染色体隐性复杂遗传性痉挛性截瘫（CHSP）的新形式。脑和脊髓MRI检查正常。在单个显著连锁位点中，作者最终在液泡蛋白分选37A （Vps37A）基因中发现了一个纯合错义突变c.1146A b> T (p.K382N)，该突变在两个家族中都具有完全渗透性和分离性。在注射了vs37a敲低morpholino寡核苷酸的斑马鱼中，活动力显著降低，支持了该基因突变与本研究患者中描述的表型之间的因果关系。结论：作者提供的证据表明，内体转运所需分选复合体（ESCRT）系统的成员Vps37A参与上运动神经元疾病。ESCRT系统已被证明在细胞内运输、多泡体成熟和泛素化膜蛋白分选到腔内囊泡中发挥核心作用。对该基因功能障碍导致CHSP的机制的进一步研究将有助于理解ESCRT机制对囊泡的细胞内运输及其与CHSP的相关性。
Background Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis.Methods The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish.Results The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A (Vps37A) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study.Conclusions The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.