Mauri Nico, Kleiter Miriam, Dietschi Elisabeth, Leschnik Michael, Högler Sandra, Wiedmer Michaela, Dietrich Joëlle, Henke Diana, Steffen Frank, Schuller Simone, Gurtner Corinne, Stokar-Regenscheit Nadine, O'Toole Donal, Bilzer Thomas, Herden Christiane, Oevermann Anna, Jagannathan Vidhya, Leeb Tosso
Institute of Genetics, Vetsuisse Faculty, University of Bern, 3001, Switzerland.
Department for Companion Animals and Horses, University Clinic for Small Animals, University of Veterinary Medicine Vienna, 1210, Austria.
G3 (Bethesda). 2017 Aug 7;7(8):2729-2737. doi: 10.1534/g3.117.043018.
Spongy degeneration with cerebellar ataxia (SDCA) is a genetically heterogeneous neurodegenerative disorder with autosomal recessive inheritance in Malinois dogs, one of the four varieties of the Belgian Shepherd breed. Using a combined linkage and homozygosity mapping approach we identified an ∼10.6 Mb critical interval on chromosome 5 in a Malinois family with four puppies affected by cerebellar dysfunction. Visual inspection of the 10.6 Mb interval in whole-genome sequencing data from one affected puppy revealed a 227 bp SINE insertion into the gene encoding the β subunit of the Na/K-ATPase holoenzyme (:c.130_131insLT796559.1:g.50_276). The SINE insertion caused aberrant RNA splicing. Immunohistochemistry suggested a reduction of ATP1B2 protein expression in the central nervous system of affected puppies. knockout mice had previously been reported to show clinical and neurohistopathological findings similar to the affected Malinois puppies. Therefore, we consider :c.130_131ins227 the most likely candidate causative variant for a second subtype of SDCA in Malinois dogs, which we propose to term spongy degeneration with cerebellar ataxia subtype 2 (SDCA2). Our study further elucidates the genetic and phenotypic complexity underlying cerebellar dysfunction in Malinois dogs and provides the basis for a genetic test to eradicate one specific neurodegenerative disease from the breeding population in Malinois and the other varieties of the Belgian Shepherd breed. thus represents another candidate gene for human inherited cerebellar ataxias, and SDCA2-affected Malinois puppies may serve as a naturally occurring animal model for this disorder.
海绵状变性伴小脑共济失调（SDCA）是一种基因异质性神经退行性疾病，在比利时牧羊犬四个品种之一的马林诺斯犬中呈常染色体隐性遗传。我们采用连锁分析和纯合性定位相结合的方法，在一个有4只幼犬受小脑功能障碍影响的马林诺斯犬家族中，确定了5号染色体上一个约10.6 Mb的关键区间。对一只患病幼犬全基因组测序数据中10.6 Mb区间的可视化检查发现，在编码Na/K - ATP酶全酶β亚基的基因中插入了一个227 bp的短散在核元件（SINE）（:c.130_131insLT796559.1:g.50_276）。该SINE插入导致异常的RNA剪接。免疫组化显示患病幼犬中枢神经系统中ATP1B2蛋白表达减少。此前报道的基因敲除小鼠表现出与患病马林诺斯幼犬相似的临床和神经组织病理学特征。因此，我们认为:c.130_131ins227是马林诺斯犬SDCA第二种亚型最可能的候选致病变异，我们提议将其命名为海绵状变性伴小脑共济失调2型（SDCA2）。我们的研究进一步阐明了马林诺斯犬小脑功能障碍背后的遗传和表型复杂性，并为从马林诺斯犬及比利时牧羊犬其他品种的繁殖群体中根除一种特定神经退行性疾病的基因检测提供了基础。因此，它是人类遗传性小脑共济失调的另一个候选基因，受SDCA2影响的马林诺斯幼犬可能作为这种疾病的天然动物模型。
