Gharahkhani Puya, O'Leary Caroline A, Duffy David L, Kyaw-Tanner Myat
Department of Genetic Epidemiology QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia 2School of Veterinary Science, University of Queensland, Gatton, Queensland, Australia.
Veterinary Medical Centre, School of Veterinary Science, University of Queensland, Gatton, Queensland, Australia.
Invest Ophthalmol Vis Sci. 2015 Dec;56(13):8288-96. doi: 10.1167/iovs.15-18074.
Primary lens luxation (PLL) in dogs is an inherited disease in which the lens is displaced from its normal position. A truncating mutation in the ADAMTS17 orthologue on CFA03 is reported to cause PLL in several breeds, mostly terriers. However, the complex inheritance pattern of PLL in miniature bull terriers (MBTs) suggests that other loci may have a modifying effect on the ADAMTS17 mutation. This study aimed to detect such loci increasing risk of PLL in Australian MBTs.
More than 170,000 single-nucleotide polymorphisms (SNPs) across the canine genome were genotyped in 23 PLL-affected and 73 normal Australian MBTs, and association between the PLL phenotype and the genetic markers was investigated by using general mixed effects Cox model survival analysis.
The highest association peaks, other than that associated with the ADAMTS17 mutation (P = 2.2e-05), were SNP BICF2G630420272 located at 62.2 Mb on chromosome 15 (P = 7.8e-05) and the region between 30 Mb and 32.5 Mb on chromosome 1 (P = 9.3e-05). Joint analysis showed that the PLL-associated allele of the BICF2G630420272 SNP increased risk of PLL in the presence of the ADAMTS17 mutation (P = 8.117e-04). Candidate genes in the two regions of interest included CPE on chromosome 15 and CTGF on chromosome 1. The ADAMTS17 mutation was also associated with abnormal foot and nail shapes, pedal hyperkeratosis, and persistent pupillary membranes.
Two loci with potentially enhancing effects on the ADAMTS17 mutation were associated with PLL in Australian MBTs. Association of the ADAMTS17 mutation with possible pedal skeletal abnormalities in MBTs supports PLL in this breed and Weill-Marchesani syndrome-like disease in humans as being homologous diseases.
犬原发性晶状体脱位（PLL）是一种遗传性疾病，晶状体从其正常位置移位。据报道，犬第3号常染色体（CFA03）上ADAMTS17同源基因的截短突变在几个品种（主要是梗犬）中会导致PLL。然而，迷你牛头梗（MBT）中PLL复杂的遗传模式表明，其他基因座可能对ADAMTS17突变有修饰作用。本研究旨在检测澳大利亚MBT中增加PLL风险的此类基因座。
对23只患PLL的和73只正常的澳大利亚MBT进行犬类基因组中超过170,000个单核苷酸多态性（SNP）的基因分型，并使用一般混合效应Cox模型生存分析研究PLL表型与遗传标记之间的关联。
除了与ADAMTS17突变相关的最高关联峰（P = 2.2×10⁻⁵）外，还有位于15号染色体62.2 Mb处的SNP BICF2G630420272（P = 7.8×10⁻⁵）以及1号染色体上30 Mb至32.5 Mb之间的区域（P = 9.3×10⁻⁵）。联合分析表明，在存在ADAMTS17突变的情况下，BICF2G630420272 SNP的PLL相关等位基因会增加PLL风险（P = 8.117×10⁻⁴）。两个感兴趣区域的候选基因包括15号染色体上的CPE和1号染色体上的CTGF。ADAMTS17突变还与足部和指甲形状异常、足垫角化过度以及持久性瞳孔膜有关。
在澳大利亚MBT中，两个对ADAMTS17突变可能有增强作用的基因座与PLL相关。ADAMTS17突变与MBT可能的足部骨骼异常相关，支持该品种的PLL以及人类的类似Weill-Marchesani综合征的疾病为同源疾病。
