Nonsense variant in COL7A1 causes recessive dystrophic epidermolysis bullosa in Central Asian Shepherd dogs.
Nonsense variant in COL7A1 causes recessive dystrophic epidermolysis bullosa in Central Asian Shepherd dogs.
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DOI：
10.1371/journal.pone.0177527
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Hytönen MK
中科院分区：
文献类型：
--
作者：
Niskanen J;Dillard K;Arumilli M;Salmela E;Anttila M;Lohi H;Hytönen MK
一种罕见的遗传性机械性大疱性疾病，称为大疱性表皮松解症 (EB)，会导致皮肤和粘膜起水泡。迄今为止，已在人类和其他物种中发现了 19 个 EB 相关基因。我们在这里描述了狗的一种新的 EB 变体。两只新生的中亚牧羊犬同窝出现严重皮肤起泡迹象，被送往兽医诊所并因预后不良而被安乐死。尸检显示，幼犬的皮肤和粘膜具有 EB 特征。对其中一只受影响的小狗进行了全基因组测序，以确定遗传原因。重测序数据在隐性模型下针对其他 31 个狗基因组的变异进行过滤，揭示了已知 EB 致病基因之一 COL7A1 (c.4579C>T，p.R1527*) 中的纯合病例特异性无义变异。该变异导致受影响的狗的皮肤基底膜中出现过早的终止密码子，并且可能缺乏功能性蛋白质。使用 COL7A1 抗体通过免疫组织化学证实了这一点。对变体的额外筛选表明，携带频率约为 28%，具有完全外显率和品种特异性。总之，这项研究揭示了一种导致隐性营养不良 EB 的新型 COL7A1 变异，并为从品种中根除该疾病提供了基因测试。
A rare hereditary mechanobullous disorder called epidermolysis bullosa (EB) causes blistering in the skin and the mucosal membranes. To date, nineteen EB-related genes have been discovered in human and other species. We describe here a novel EB variant in dogs. Two newborn littermates of Central Asian Shepherd dogs with severe signs of skin blistering were brought to a veterinary clinic and euthanized due to poor prognosis. In post-mortem examination, the puppies were shown to have findings in the skin and the mucosal membranes characteristic of EB. A whole-genome sequencing of one of the affected puppies was performed to identify the genetic cause. The resequencing data were filtered under a recessive model against variants from 31 other dog genomes, revealing a homozygous case-specific nonsense variant in one of the known EB-causing genes, COL7A1 (c.4579C>T, p.R1527*). The variant results in a premature stop codon and likely absence of the functional protein in the basement membrane of the skin in the affected dogs. This was confirmed by immunohistochemistry using a COL7A1 antibody. Additional screening of the variant indicated full penetrance and breed specificity at ~28% carrier frequency. In summary, this study reveals a novel COL7A1 variant causing recessive dystrophic EB and provides a genetic test for the eradication of the disease from the breed.