A Non-Synonymous Mutation in the Canine <em>Pkd1</em> Gene Is Associated with Autosomal Dominant Polycystic Kidney Disease in Bull Terriers

Polycystic Kidney Disease is an autosomal dominant disease common in some lines of Bull Terriers (BTPKD). The disease is linked to the canine orthologue of human PKD1 gene, Pkd1, located on CFA06, but no disease-associated mutation has been reported. This study sequenced genomic DNA from two Bull Terriers with BTPKD and two without the disease. A non-synonymous G>A transition mutation in exon 29 of Pkd1 was identified. A TaqMan® SNP Genotyping Assay was designed and demonstrated the heterozygous detection of the mutation in 47 Bull Terriers with BTPKD, but not in 102 Bull Terriers over one year of age and without BTPKD. This missense mutation replaces a glutamic acid residue with a lysine residue in the predicted protein, Polycystin 1. This region of Polycystin 1 is highly conserved between species, and is located in the first cytoplasmic loop of the predicted protein structure, close to the PLAT domain and the second transmembrane region. Thus, this change could alter Polycystin 1 binding or localization. Analytic programs PolyPhen 2, Align GVGD and SIFT predict this mutation to be pathogenic. Thus, BTPKD is associated with a missense mutation in Pkd1, and the application of this mutation specific assay could reduce disease transmission by allowing diagnosis of disease in young animals prior to breeding.多囊肾病（Polycystic Kidney Disease）是一类常染色体显性遗传病，在部分牛头㹴（Bull Terrier）品系中高发，该病症又称牛头㹴多囊肾病（BTPKD）。该病与人类PKD1基因的犬类同源基因Pkd1相关，该基因定位于CFA06，但目前尚未有与疾病相关的突变被报道。本研究对2头确诊BTPKD的牛头㹴与2头健康牛头㹴的基因组DNA进行了测序。研究人员在Pkd1基因的第29号外显子中发现了一处非同义G>A转换突变。研究团队设计了TaqMan® SNP基因分型检测试剂盒，该试剂盒可在47头患BTPKD的牛头㹴样本中检测到该突变的杂合状态，但在102头年满1岁且未患BTPKD的牛头㹴样本中未检测到该突变。该错义突变会使预测得到的多囊蛋白1（Polycystin 1）序列中的谷氨酸残基替换为赖氨酸残基。多囊蛋白1的该区域在不同物种间高度保守，且位于预测蛋白结构的首个胞质环内，紧邻PLAT结构域与第二个跨膜区域。因此，该突变可能会改变多囊蛋白1的结合特性或亚细胞定位。PolyPhen 2、Align GVGD以及SIFT等生物信息学分析软件均预测该突变具有致病性。综上，BTPKD与Pkd1基因的一处错义突变密切相关，利用该突变特异性检测试剂盒可在幼崽繁育前完成疾病诊断，从而有效降低该病的传播风险。