Recessive TRAPPC11 Mutations Cause a Disease Spectrum of Limb Girdle Muscular Dystrophy and Myopathy with Movement Disorder and Intellectual Disability
Recessive TRAPPC11 Mutations Cause a Disease Spectrum of Limb Girdle Muscular Dystrophy and Myopathy with Movement Disorder and Intellectual Disability
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DOI：
10.1016/j.ajhg.2013.05.028
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发表时间：
2013-07-11
影响因子：
9.8
通讯作者：
Lamont, Ryan E.
中科院分区：
文献类型：
--
作者：
Boegershausen, Nina;Shahrzad, Nassim.;Lamont, Ryan E.
肌病是一组临床和病因不同的疾病，范围从四肢带状肌营养不良(LGMD)到具有相关特征的综合征形式，包括智能障碍。在这里，我们报告了在一个患有LGMD的血缘叙利亚家庭的三个人和表现为肌病、婴儿多动运动、共济失调和智力残疾的五个哈特利人后裔的个体中发现了运输蛋白颗粒复合体11(TRAPPC11)的突变。通过全外显子组或基因组测序与纯合性图谱相结合的方法，我们在叙利亚LGMD家族中发现了TRAPPC11的gryzun结构域中的c.2938G>；A(p.Gly980Arg)错义突变，并在Hutterite家族中发现了导致TRAPPC11的鹅肝酱结构域中58个氨基酸残基缺失的剪接点突变(p.Ala372_Ser429del)。TRAPPC11编码参与膜转运的多蛋白TRapp复合体的一个组成部分。我们证明这两个突变都损害了TRAPPC11与其他TRapp复杂成分的结合能力，并破坏了高尔基体的结构。对p.Ala372_Ser429del缺失的标记转运实验表明，内质网到高尔基体的转运是正常的，但显著延迟了从高尔基体到细胞表面的出口。此外，我们观察到由于TRAPPC11功能障碍导致溶酶体膜糖蛋白溶酶体相关膜蛋白1(LAMP1)和LAMP2的改变，支持分泌蛋白运输的缺陷是潜在的致病机制。
Myopathies are a clinically and etiologically heterogeneous group of disorders that can range from limb girdle muscular dystrophy (LGMD) to syndromic forms with associated features including intellectual disability. Here, we report the identification of mutations in transport protein particle complex 11 (TRAPPC11) in three individuals of a consanguineous Syrian family presenting with LGMD and in five individuals of Hutterite descent presenting with myopathy, infantile hyperkinetic movements, ataxia, and intellectual disability. By using a combination of whole-exome or genome sequencing with homozygosity mapping, we identified the homozygous c.2938G>A (p.Gly980Arg) missense mutation within the gryzun domain of TRAPPC11 in the Syrian LGMD family and the homozygous c.1287+5G>A splice-site mutation resulting in a 58 amino acid in-frame deletion (p.Ala372_Ser429del) in the foie gras domain of TRAPPC11 in the Hutterite families. TRAPPC11 encodes a component of the multiprotein TRAPP complex involved in membrane trafficking. We demonstrate that both mutations impair the binding ability of TRAPPC11 to other TRAPP complex components and disrupt the Golgi apparatus architecture. Marker trafficking experiments for the p.Ala372_Ser429del deletion indicated normal ER-to-Golgi trafficking but dramatically delayed exit from the Golgi to the cell surface. Moreover, we observed alterations of the lysosomal membrane glycoproteins lysosome-associated membrane protein 1 (LAMP1) and LAMP2 as a consequence of TRAPPC11 dysfunction supporting a defect in the transport of secretory proteins as the underlying pathomechanism.