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A putative silencer variant in a spontaneous canine model of retinitis pigmentosa.
PLOS Genetics ( IF 4.5 ) Pub Date : 2020-03-09 , DOI: 10.1371/journal.pgen.1008659
Maria Kaukonen 1, 2, 3 , Ileana B Quintero 1, 2, 3 , Abdul Kadir Mukarram 4 , Marjo K Hytönen 1, 2, 3 , Saila Holopainen 1, 2, 3, 5 , Kaisa Wickström 6 , Kaisa Kyöstilä 1, 2, 3 , Meharji Arumilli 1, 2, 3 , Sari Jalomäki 7 , Carsten O Daub 4, 8 , Juha Kere 3, 4, 9 , Hannes Lohi 1, 2, 3 ,
Affiliation  

Retinitis pigmentosa (RP) is the leading cause of blindness with nearly two million people affected worldwide. Many genes have been implicated in RP, yet in 30–80% of the RP patients the genetic cause remains unknown. A similar phenotype, progressive retinal atrophy (PRA), affects many dog breeds including the Miniature Schnauzer. We performed clinical, genetic and functional experiments to identify the genetic cause of PRA in the breed. The age of onset and pattern of disease progression suggested that at least two forms of PRA, types 1 and 2 respectively, affect the breed, which was confirmed by genome-wide association study that implicated two distinct genomic loci in chromosomes 15 and X, respectively. Whole-genome sequencing revealed a fully segregating recessive regulatory variant in type 1 PRA. The associated variant has a very recent origin based on haplotype analysis and lies within a regulatory site with the predicted binding site of HAND1::TCF3 transcription factor complex. Luciferase assays suggested that mutated regulatory sequence increases expression. Case-control retinal expression comparison of six best HAND1::TCF3 target genes were analyzed with quantitative reverse-transcriptase PCR assay and indicated overexpression of EDN2 and COL9A2 in the affected retina. Defects in both EDN2 and COL9A2 have been previously associated with retinal degeneration. In summary, our study describes two genetically different forms of PRA and identifies a fully penetrant variant in type 1 form with a possible regulatory effect. This would be among the first reports of a regulatory variant in retinal degeneration in any species, and establishes a new spontaneous dog model to improve our understanding of retinal biology and gene regulation while the affected breed will benefit from a reliable genetic testing.



中文翻译:

色素性视网膜炎的自发犬模型中的推定消音变异体。

色素性视网膜炎(RP)是失明的主要原因,全世界有近200万人受到影响。RP中涉及许多基因,但在30-80%的RP患者中,遗传原因仍然未知。类似的表型,进行性视网膜萎缩(PRA),会影响许多犬种,包括迷你雪纳瑞犬。我们进行了临床,遗传和功能实验,以确定该品种PRA的遗传原因。发病年龄和疾病进展模式表明,至少两种形式的PRA(分别为1型和2型)会影响该品种,这一点已通过全基因组关联研究得到证实,该研究分别涉及15号和X号染色体上的两个不同的基因组位点。 。全基因组测序显示1型PRA中完全隔离的隐性调节变异。相关的变体基于单倍型分析具有非常新的起源,并且位于具有预测的HAND1 :: TCF3转录因子复合物结合位点的调控位点内。萤光素酶测定法表明,突变的调控序列可增加表达。案例对照视网膜表达的六个最佳HAND1 :: TCF3靶基因的比较进行了定量逆转录PCR分析,并表明受影响的视网膜中的EDN2COL9A2EDN2COL9A2的缺陷先前都与视网​​膜变性有关。总而言之,我们的研究描述了PRA的两种遗传上不同的形式,并鉴定了可能具有调节作用的1型完全渗透变体。这将是关于任何物种视网膜变性的调控变异的第一份报道之一,并建立了一种新的自发犬模型,以增进我们对视网膜生物学和基因调控的理解,同时受影响的品种将从可靠的基因测试中受益。

更新日期:2020-04-06
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