Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy
Biallelic Variants in TTLL5, Encoding a Tubulin Glutamylase, Cause Retinal Dystrophy
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DOI：
10.1016/j.ajhg.2014.04.003
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发表时间：
2014-05-01
影响因子：
9.8
通讯作者：
Plagnol, Vincent
中科院分区：
文献类型：
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作者：
Sergouniotis, Panagiotis I.;Chakarova, Christina;Plagnol, Vincent
在遗传性视网膜变性（包括视锥、视锥-视杆和黄斑营养不良）的一个子集中，视锥光感受器比视杆受到更严重的影响; ABCA 4突变是这种异质性疾病的最常见原因。为了鉴定视网膜疾病相关基因，我们对28名患有“视锥细胞优先”视网膜疾病和ABCA 4视网膜病变非典型临床特征的个体进行了外显子组测序。然后，我们进行了一个基于基因的病例对照关联研究与内部外显子组数据集作为对照组。编码微管蛋白谷氨酰胺酶的TILLS被强调为最可能的疾病相关基因; 28名受影响的受试者中有2名携带假定的功能丧失变体：c. [1586 1589delAGAG];[1586_1589delAGAG]，p. [Glu 529 Valfs（星星）2];[Glu 529 Valfs（星星）2]，和c. [401delT（;）3354G>A]，p. [Leu 134 Argfs（星星）45（;）Trp 1118（星星）].然后，我们检查了先前收集的具有相关表型的个体的外显子组序列数据，并在TILLS中发现了两个具有纯合无义变体c.1627 G>T（p.Glu543（星星））的兄弟姐妹。随后，我们检测了一组55名视网膜营养不良先证者的TILLS突变;一名先证者有纯合子错义改变（c.1627G>A [p.Glu543Lys]）。四个家族中有三个的视网膜表型高度相似;兄弟姐妹对有更严重的早发性疾病。在人类和小鼠视网膜中，TTLL 5定位于连接纤毛基部的中心粒。TILLS在小鼠精子鞭毛的正常功能中起重要作用，并在体外初级纤毛的多聚谷氨酰化中发挥作用。值得注意的是，参与微管蛋白的多聚谷氨酰化和去谷氨酰化的基因与小鼠的光感受器变性有关。电生理和眼底自发荧光成像有助于进一步的分子诊断。
In a subset of inherited retinal degenerations (including cone, cone-rod, and macular dystrophies), cone photoreceptors are more severely affected than rods; ABCA4 mutations are the most common cause of this heterogeneous class of disorders. To identify retinal-disease-associated genes, we performed exome sequencing in 28 individuals with "cone-first" retinal disease and clinical features atypical for ABCA4 retinopathy. We then conducted a gene-based case-control association study with an internal exome data set as the control group. TILLS, encoding a tubulin glutamylase, was highlighted as the most likely disease-associated gene; 2 of 28 affected subjects harbored presumed loss-of-function variants: c.[1586_1589delAGAG];[1586_1589delAGAG], p.[Glu529Valfs(star)2];[Glu529Valfs(star)2], and c.[401delT(;) 3354G>A], p.[Leu134Argfs(star)45(;)Trp1118(star)]. We then inspected previously collected exome sequence data from individuals with related phenotypes and found two siblings with homozygous nonsense variant c.1627G>T (p.Glu543(star)) in TILLS. Subsequently, we tested a panel of 55 probands with retinal dystrophy for TILLS mutations; one proband had a homozygous missense change (c.1627G>A [p.Glu543Lys]). The retinal phenotype was highly similar in three of four families; the sibling pair had a more severe, early-onset disease. In human and murine retinae, TTLL5 localized to the centrioles at the base of the connecting cilium. TILLS has been previously reported to be essential for the correct function of sperm flagella-in mice and play a role in polyglutamylation of primary cilia in vitro. Notably, genes involved in the polyglutamylation and deglutamylation of tubulin have been associated with photoreceptor degeneration in mice. The electrophysiological and fundus autofluorescence imaging presented here should facilitate the molecular diagnosis in further families.