Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia
Truncating Mutations in UBAP1 Cause Hereditary Spastic Paraplegia
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DOI：
10.1016/j.ajhg.2019.03.001
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发表时间：
2019-04-04
影响因子：
9.8
通讯作者：
Faghihi, Mohammad Ali
中科院分区：
文献类型：
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作者：
Fard, Mohammad Ali Farazi;Rebelo, Adriana P.;Faghihi, Mohammad Ali
尽管基因鉴定不断取得进展，但罕见神经退行性疾病的诊断差距仍然很大。许多新的孟德尔基因仅在全球少数几个家族中被发现。在这里，我们报告了在 10 个具有不同地理起源的家族中鉴定出遗传性痉挛性截瘫 (HSP) 的常染色体显性基因，这些家族的受影响成员都在 UBAP1（泛素相关蛋白 1）的外接区域中携带独特的截短变化。 HSP 是一种神经退行性疾病，其特征是进行性下肢痉挛和无力，以及频繁的膀胱功能障碍。目前，至少 40% 的受影响者在外显子组测序后仍未确诊。我们在来自伊朗、美国、德国、加拿大、西班牙和保加利亚罗姆人的受影响人群中发现了 UBAP1 的病理性截短变异。遗传支持范围从最大家族的连锁 (LOD = 8.3) 到三个已确认的从头突变。我们发现，受影响个体的成纤维细胞中的 mRNA 逃脱了无义介导的衰变，从而导致截短蛋白的表达；此外，与对照相比，全长蛋白质的浓度有所降低。这表明显性负效应或单倍体不足。 UBAP1 将内体运输与先前与 HSP 相关的泛素化机制通路联系起来，并且 UBAP1 为更统一的病理生理学提供了一座桥梁。
The diagnostic gap for rare neurodegenerative diseases is still considerable, despite continuous advances in gene identification. Many novel Mendelian genes have only been identified in a few families worldwide. Here we report the identification of an autosomal-dominant gene for hereditary spastic paraplegia (HSP) in 10 families that are of diverse geographic origin and whose affected members all carry unique truncating changes in a circumscript region of UBAP1 (ubiquitin-associated protein 1). HSP is a neurodegenerative disease characterized by progressive lower-limb spasticity and weakness, as well as frequent bladder dysfunction. At least 40% of affected persons are currently undiagnosed after exome sequencing. We identified pathological truncating variants in UBAP1 in affected persons from Iran, USA, Germany, Canada, Spain, and Bulgarian Roma. The genetic support ranges from linkage in the largest family (LOD = 8.3) to three confirmed de novo mutations. We show that mRNA in the fibroblasts of affected individuals escapes nonsense-mediated decay and thus leads to the expression of truncated proteins; in addition, concentrations of the full-length protein are reduced in comparison to those in controls. This suggests either a dominant-negative effect or haploinsufficiency. UBAP1 links endosomal trafficking to the ubiquitination machinery pathways that have been previously implicated in HSPs, and UBAP1 provides a bridge toward a more unified pathophysiology.