Department of Veterinary Pathobiology, University of Missouri College of Veterinary Medicine, Columbia, MO, USA.
Metz Petz Veterinary Clinic at Shawnee, Lima, OH, USA.
Mol Genet Metab. 2014 Aug;112(4):302-9. doi: 10.1016/j.ymgme.2014.05.014. Epub 2014 Jun 4.
The neuronal ceroid lipofuscinoses (NCLs) are hereditary neurodegenerative diseases characterized by seizures and progressive cognitive decline, motor impairment, and vision loss accompanied by accumulation of autofluorescent lysosomal storage bodies in the central nervous system and elsewhere in the body. Mutations in at least 14 genes underlie the various forms of NCL. One of these genes, CLN8, encodes an intrinsic membrane protein of unknown function that appears to be localized primarily to the endoplasmic reticulum. Most CLN8 mutations in people result in a form of NCL with a late infantile onset and relatively rapid progression. A mixed breed dog with Australian Shepherd and Blue Heeler ancestry developed neurological signs characteristic of NCL starting at about 8months of age. The signs became progressively worse and the dog was euthanized at 21months of age due to seizures of increasing frequency and severity. Postmortem examination of the brain and retinas identified massive accumulations of intracellular autofluorescent inclusions characteristic of the NCLs. Whole genome sequencing of DNA from this dog identified a CLN8:c.585G>A transition that predicts a CLN8:p.Trp195* nonsense mutation. This mutation appears to be rare in both ancestral breeds. All of our 133 archived DNA samples from Blue Heelers, and 1481 of our 1488 archived Australian Shepherd DNA samples tested homozygous for the reference CLN8:c.585G allele. Four of the Australian Shepherd samples tested heterozygous and 3 tested homozygous for the mutant CLN8:c.585A allele. All 3 dogs homozygous for the A allele exhibited clinical signs of NCL and in 2 of them NCL was confirmed by postmortem evaluation of brain tissue. The occurrence of confirmed NCL in 3 of 4 CLN8:c.585A homozygous dogs, plus the occurrence of clinical signs consistent with NCL in the fourth homozygote strongly suggests that this rare truncating mutation causes NCL. Identification of this NCL-causing mutation provides the opportunity for identifying dogs that can be used to establish a canine model for the CLN8 disease (also known as late infantile variant or late infantile CLN8 disease).
神经元蜡样脂褐质沉积症（NCLs）是遗传性神经退行性疾病，其特征是癫痫发作和进行性认知能力下降、运动障碍以及视力丧失，同时伴有中枢神经系统和身体其他部位的自体荧光溶酶体贮积物积累。至少有 14 种基因突变导致了各种形式的 NCL。其中一个基因 CLN8 编码一种未知功能的内在膜蛋白，该蛋白似乎主要定位于内质网。人类中大多数 CLN8 突变导致晚发性婴儿型 NCL，其进展相对较快。一只具有澳大利亚牧羊犬和蓝色赫勒尔血统的杂种狗，从大约 8 个月大开始出现 NCL 特征性的神经症状。症状逐渐恶化，由于癫痫发作的频率和严重程度不断增加，该犬在 21 个月大时被安乐死。对大脑和视网膜进行的尸检发现了大量的细胞内自体荧光内含物，这些内含物是 NCL 的特征。对这只狗的 DNA 进行全基因组测序，发现了 CLN8:c.585G>A 转换，预测了 CLN8:p.Trp195*无义突变。这种突变在两个祖先后代品种中似乎都很罕见。我们所有的 133 份蓝色赫勒尔犬的存档 DNA 样本和 1488 份澳大利亚牧羊犬存档 DNA 样本中，有 1481 份为 CLN8:c.585G 等位基因的纯合子。有 4 份澳大利亚牧羊犬样本为杂合子，3 份为 CLN8:c.585A 等位基因的纯合子。所有 3 只携带 A 等位基因的澳大利亚牧羊犬均表现出 NCL 的临床症状，其中 2 只的脑组织通过尸检得到了确认。在 4 只 CLN8:c.585A 纯合子犬中，有 3 只确诊为 NCL，第四只纯合子犬出现了与 NCL 一致的临床症状，这强烈表明这种罕见的截断突变导致了 NCL。这种 NCL 致病突变的鉴定为寻找可用于建立 CLN8 疾病（也称为晚发性婴儿型或晚发性婴儿 CLN8 疾病）犬模型的犬提供了机会。
