Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy
Mutations in BICD2, which Encodes a Golgin and Important Motor Adaptor, Cause Congenital Autosomal-Dominant Spinal Muscular Atrophy
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DOI：
10.1016/j.ajhg.2013.04.011
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发表时间：
2013-06-06
影响因子：
9.8
通讯作者：
Wirth, Brunhilde
中科院分区：
文献类型：
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作者：
Neveling, Kornelia;Martinez-Carrera, Lilian A.;Wirth, Brunhilde
脊髓性肌萎缩症(SMA)是一组由下运动神经元变性引起的异质性神经肌肉疾病。虽然SMN1的功能丧失与儿童常染色体隐性遗传的SMA有关，但大多数受显性遗传性SMA影响的家庭的遗传原因尚不清楚。在这里，我们在三个患有常染色体显性SMA的家庭中发现了双尾状D同源基因2(果蝇)(BICD2)的致病变异。受累个体表现为先天性缓慢进行性肌肉无力，主要表现为下肢和先天性肌挛缩。在一个荷兰大家庭中，连锁分析发现了一个9q22.3基因座，其中外显子测序发现了BICD2中的c.320C>；T(p.Ser107Leu)。对另外23个受显性SMA影响的家系进行测序后，在来自加拿大的一个家系(c.2108C>；T[p.Thr703Met])和来自荷兰的一个家系(c.563A>；C[p.Asn188Thr])中发现了致病变异。BICD2是一种高尔京蛋白和运动适配蛋白，参与高尔基体动力学、囊泡和mRNA的运输。瞬时将三个突变型BICD2cDNA导入HeLa细胞，可引起大量高尔基体碎裂。这一观察结果在含有c.2108C>；T(p.Thr703Met)(影响C末端螺旋线圈结构域)的个体的原代成纤维细胞中更加明显，而在携带c.563A>；C(p.Asn188Thr)(影响N端螺旋线圈结构域)的个体中略不明显。此外，在受影响的个体中，BICD2水平降低，并被困在支离破碎的高尔基体中。以前的研究表明，果蝇突变体BicD通过破坏神经肌肉接头上的网状蛋白介导的突触内吞作用，导致幼虫运动减少。这些数据强调了BICD2在突触-囊泡循环中的相关性，并支持了BICD2突变导致先天性缓慢进展的显性SMA的结论。
Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of He La cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.