PDF(Pubmed)
Abstract：
Progressive retinal atrophies (PRAs) are a genetically heterogeneous group of inherited eye diseases that affect over 100 breeds of dog. The initial clinical sign is visual impairment in scotopic conditions, as a consequence of rod photoreceptor cell degeneration. Photopic vision degeneration then follows, due to progression of the disease to the cone photoreceptors, and ultimately results in complete blindness. Two full-sibling English Shepherds were diagnosed with PRA at approximately 5 years old and tested clear of all published PRA genetic variants. This study sought to identify the novel PRA-associated variant segregating in the breed. We utilised a combined approach of whole genome sequencing of the probands and homozygosity mapping of four cases and 22 controls and identified a short interspersed nuclear element within an alternatively spliced exon in FAM161A. The XP_005626197.1 c.17929_ins210 variant was homozygous in six PRA cases and heterozygous or absent in control dogs, consistent with a recessive mode of inheritance. The insertion is predicted to extend exon 4 by 39 aberrant amino acids followed by an early termination stop codon. PRA is intractable to treatment, so the development of a genetic screening test, based on the associated variant, is significant, because it provides dog breeders/owners with a means of reducing the frequency of the disease variant within this breed as well as minimising the risk of breeding puppies that will develop this blinding disease.
摘要：
进行性视网膜萎缩(PRAs)是一组遗传异质性的遗传性眼病,其影响超过100个品种的狗。最初的临床症状是暗视条件下的视力障碍，视杆感光细胞变性的结果。接着是视力退化，由于疾病进展到视锥光感受器，最终导致完全失明。两个完整的兄弟姐妹英国牧羊犬在大约5岁时被诊断出患有PRA，并检测出所有已发表的PRA遗传变异。这项研究试图鉴定该品种中分离的新型PRA相关变体。我们利用了先证者的全基因组测序和4例病例和22例对照的纯合性作图的组合方法，并在FAM161A的可变剪接外显子中鉴定了一个短散布的核元素。XP_005626197.1c.17929_ins210变体在6例PRA病例中是纯合的，在对照犬中是杂合的或不存在，与隐性继承模式一致。预测插入将外显子4延伸39个异常氨基酸,随后是早期终止终止密码子。PRA难以治疗，所以基因筛查测试的发展，基于相关的变体，意义重大，因为它为狗饲养者/主人提供了一种方法，可以减少该品种中疾病变异的频率，并将繁殖幼犬的风险降至最低，这些幼犬会患上这种致盲疾病。
