An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates.
An EHPB1L1 Nonsense Mutation Associated with Congenital Dyserythropoietic Anemia and Polymyopathy in Labrador Retriever Littermates.
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在本报告中，我们描述了拉布拉多猎犬同窝幼犬先天性红细胞生成不良性贫血和多发性肌病的一种新型遗传基础，其特征为偶然检测到显著的小红细胞症、不适当的晚幼红细胞增多症、后肢无力以及肌肉萎缩。在英国史宾格猎犬同窝幼犬中也描述了一种类似的综合征，表现为早期出现贫血、巨食管、全身性肌肉萎缩和心肌病。这两个品种的肌肉组织病理学均显示出与先天性多发性肌病一致的独特病理变化。通过全基因组测序并比对到CanFam4（家犬参考基因组组装4），在拉布拉多猎犬同窝幼犬中鉴定出EHBP1L1基因的一个无义变异，为纯合形式。该突变产生一个提前终止密码子，导致大约90%的蛋白质缺失。这种变异在英国史宾格猎犬中不存在。目前，EHPB1L1被描述为对极化上皮细胞中肌动蛋白细胞骨架组织和顶端定向运输至关重要，并且通过与Rab8和一个BIN1 - 动力蛋白复合物的连接，在内吞再循环区室中产生膜泡。此外，EHBP1L1基因敲除小鼠早亡并出现严重贫血。由于BIN1和DMN2突变是某些形式的中央核肌病的病因，EHBP1L1与BIN1和DMN2功能的联系特别令人感兴趣。本报告以及另一个小组进行的一项独立研究，是关于EHBP1L1突变与先天性红细胞生成不良性贫血和多发性肌病相关联的首次报道。
In this report, we describe a novel genetic basis for congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates characterized by incidental detection of marked microcytosis, inappropriate metarubricytosis, pelvic limb weakness and muscle atrophy. A similar syndrome has been described in English Springer Spaniel littermates with an early onset of anemia, megaesophagus, generalized muscle atrophy and cardiomyopathy. Muscle histopathology in both breeds showed distinctive pathological changes consistent with congenital polymyopathy. Using whole genome sequencing and mapping to the CanFam4 (Canis lupus familiaris reference assembly 4), a nonsense variant in the EHBP1L1 gene was identified in a homozygous form in the Labrador Retriever littermates. The mutation produces a premature stop codon that deletes approximately 90% of the protein. This variant was not present in the English Springer Spaniels. Currently, EHPB1L1 is described as critical to actin cytoskeletal organization and apical-directed transport in polarized epithelial cells, and through connections with Rab8 and a BIN1-dynamin complex generates membrane vesicles in the endocytic recycling compartment. Furthermore, EHBP1L1 knockout mice die early and develop severe anemia. The connection of EHBP1L1 to BIN1 and DMN2 functions is particularly interesting due to BIN1 and DMN2 mutations being causative in forms of centronuclear myopathy. This report, along with an independent study conducted by another group, are the first reports of an association of EHBP1L1 mutations with congenital dyserythropoietic anemia and polymyopathy.
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影响因子：
2.6
作者：
Thomas-Hollands A;Shelton GD;Guo LT;Loughran K;Kaiman G;A Hutton T;Walsh KA
通讯作者：
Walsh KA
影响因子：
20.3
作者：
Iolascon, Achille;Heimpel, Hermann;Tamary, Hannah
通讯作者：
Tamary, Hannah
影响因子：
2.4
作者：
Jagannathan, V;Droegemueller, C.;Wade, Claire
通讯作者：
Wade, Claire
影响因子：
4.5
作者：
Boehm, Johann;Vasli, Nasim;Laporte, Jocelyn
通讯作者：
Laporte, Jocelyn
影响因子：
5.3
作者：
Meurs, Kathryn M.;Friedenberg, Steven G.;Granzier, Henk
通讯作者：
Granzier, Henk