A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima
A novel TRAPPC11 mutation in two Turkish families associated with cerebral atrophy, global retardation, scoliosis, achalasia and alacrima
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DOI：
10.1136/jmedgenet-2016-104108
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发表时间：
2017-03-01
影响因子：
4
通讯作者：
Sacher, Michael
中科院分区：
文献类型：
--
作者：
Koehler, Katrin;Milev, Miroslav P.;Sacher, Michael
背景三A综合征（MIM # 231550）与AAAS基因突变有关。然而，大约30%有三A综合征症状但未确诊的患者并未携带AAAS突变。目的寻找未检测到AAAS突变的三A样表型家系中新的遗传缺陷。方法采用全基因组连锁分析、全外显子测序和功能分析等方法，在两个失弛缓症、无泪症、肌病及其他症状的家系中发现并验证一种新的遗传缺陷。结果在TRAPPC 11基因中发现了一个纯合性剪接突变（c。1893+3A > G，[NM_021942.5]，g. 4：184，607，904 A> G [hg 19]），导致不完全外显子跳跃和全长mRNA水平降低。TRAPPC 11编码运输蛋白颗粒复合物亚基11（TRAPPC 11），其为运输蛋白颗粒（TRAPP）复合物的蛋白质。Western印迹分析显示，全长TRAPPC 11蛋白水平和LAMP 1的低糖基化显著降低。在患者成纤维细胞中的贩运实验揭示了标记蛋白在高尔基体中的延迟到达以及它们从高尔基体释放到质膜的延迟。TRAPPC 11的突变先前已被描述为导致肢带型肌营养不良症2S型（MIM # 615356）。事实上，我们的患者的肌肉组织学也显示出轻度营养不良的变化。免疫组化，β-肌聚糖是不存在的局灶patchs.Conclusions确定的新TRAPPC 11突变代表了以前描述的肌病表型的扩展，其特点是特别是由失弛缓症，alacrima，神经和肌肉表型。
Background Triple A syndrome (MIM # 231550) is associated with mutations in the AAAS gene. However, about 30% of patients with triple A syndrome symptoms but an unresolved diagnosis do not harbour mutations in AAAS. Objective Search for novel genetic defects in families with a triple A-like phenotype in whom AAAS mutations are not detected.Methods Genome-wide linkage analysis, whole-exome sequencing and functional analyses were used to discover and verify a novel genetic defect in two families with achalasia, alacrima, myopathy and further symptoms. Effect and pathogenicity of the mutation were verified by cell biological studies.Results We identified a homozygous splice mutation in TRAPPC11 (c. 1893+3A > G, [NM_021942.5], g. 4: 184,607,904A > G [hg19]) in four patients from two unrelated families leading to incomplete exon skipping and reduction in full-length mRNA levels. TRAPPC11 encodes for trafficking protein particle complex subunit 11 (TRAPPC11), a protein of the transport protein particle (TRAPP) complex. Western blot analysis revealed a dramatic decrease in full-length TRAPPC11 protein levels and hypoglycosylation of LAMP1. Trafficking experiments in patient fibroblasts revealed a delayed arrival of marker proteins in the Golgi and a delay in their release from the Golgi to the plasma membrane. Mutations in TRAPPC11 have previously been described to cause limb-girdle muscular dystrophy type 2S (MIM # 615356). Indeed, muscle histology of our patients also revealed mild dystrophic changes. Immunohistochemically, beta-sarcoglycan was absent from focal patches.Conclusions The identified novel TRAPPC11 mutation represents an expansion of the myopathy phenotype described before and is characterised particularly by achalasia, alacrima, neurological and muscular phenotypes.