Department of Veterinary Pathobiology, University of Missouri, Columbia, MO, USA.
Angell Animal Medical Center, Boston, MA 02130, USA.
Mol Genet Metab. 2019 May;127(1):107-115. doi: 10.1016/j.ymgme.2019.04.003. Epub 2019 Apr 17.
The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative disorders characterized by progressive declines in neurological functions following normal development. The NCLs are distinguished from similar disorders by the accumulation of autofluorescent lysosomal storage bodies in neurons and many other cell types, and are classified as lysosomal storage diseases. At least 13 genes contain pathogenic sequence variants that underlie different forms of NCL. Naturally occurring canine NCLs can serve as models to develop better understanding of the disease pathologies and for preclinical evaluation of therapeutic interventions for these disorders. To date 14 sequence variants in 8 canine orthologs of human NCL genes have been found to cause progressive neurological disorders similar to human NCLs in 12 different dog breeds. A mixed breed dog with parents of uncertain breed background developed progressive neurological signs consistent with NCL starting at approximately 11 to 12 months of age, and when evaluated with magnetic resonance imaging at 21 months of age exhibited diffuse brain atrophy. Due to the severity of neurological decline the dog was euthanized at 23 months of age. Cerebellar and cerebral cortical neurons contained massive accumulations of autofluorescent storage bodies the contents of which had the appearance of tightly packed membranes. A whole genome sequence, generated with DNA from the affected dog contained a homozygous C-to-T transition at position 30,574,637 on chromosome 22 which is reflected in the mature CLN5 transcript (CLN5: c.619C > T) and converts a glutamine codon to a termination codon (p.Gln207Ter). The identical nonsense mutation has been previously associated with NCL in Border Collies, Australian Cattle Dogs, and a German Shepherd-Australian Cattle Dog mix. The current whole genome sequence and a previously generated whole genome sequence for an Australian Cattle Dog with NCL share a rare homozygous haplotype that extends for 87 kb surrounding 22: 30, 574, 637 and includes 21 polymorphic sites. When genotyped at 7 of these polymorphic sites, DNA samples from the German Shepherd-Australian Cattle Dog mix and from 5 Border Collies with NCL that were homozygous for the CLN5: c.619 T allele also shared this homozygous haplotype, suggesting that the NCL in all of these dogs stems from the same founding mutation event that may have predated the establishment of the modern dog breeds. If so, the CLN5 nonsence allele is probably segregating in other, as yet unidentified, breeds. Thus, dogs exhibiting similar NCL-like signs should be screened for this CLN5 nonsense allele regardless of breed.
神经元蜡样脂褐质沉积症（NCLs）是一组遗传性神经退行性疾病，其特征是在正常发育后神经功能逐渐下降。NCLs 通过神经元和许多其他细胞类型中积累自发荧光溶酶体储存体与类似疾病区分开来，并被归类为溶酶体贮积病。至少有 13 个基因包含导致不同形式 NCL 的致病序列变异。天然发生的犬 NCL 可作为模型，以更好地了解疾病病理学，并对这些疾病的临床前治疗干预措施进行评估。迄今为止，在 12 个不同的犬种中，已在 8 个犬 NCL 基因的同源物中发现了 14 个序列变异，这些变异导致类似于人类 NCL 的进行性神经疾病。一只混合品种的狗，父母的品种背景不确定，从大约 11 到 12 个月大开始出现进行性神经症状，类似于 NCL，并在 21 个月大时进行磁共振成像评估时表现出弥漫性脑萎缩。由于神经衰退的严重程度，这只狗在 23 个月大时被安乐死。小脑和大脑皮层神经元含有大量的自发荧光储存体，其内容物的外观为紧密堆积的膜。用受影响的狗的 DNA 生成的全基因组序列在 22 号染色体上的 30,574,637 位置包含一个纯合的 C 到 T 转换，这反映在成熟的 CLN5 转录本（CLN5：c.619C > T）中，并将谷氨酰胺密码子转换为终止密码子（p.Gln207Ter）。相同的无意义突变先前与边境牧羊犬、澳大利亚牧羊犬和德国牧羊犬-澳大利亚牧羊犬混合犬的 NCL 有关。目前的全基因组序列和先前对患有 NCL 的澳大利亚牧羊犬的全基因组序列共享一个罕见的纯合单倍型，该单倍型延伸 87kb 环绕 22：30,574,637 并包括 21 个多态性位点。在 7 个多态性位点进行基因分型时，德国牧羊犬-澳大利亚牧羊犬混合犬和 5 只携带 NCL 的边境牧羊犬的 DNA 样本也共享这种纯合单倍型，这表明所有这些狗的 NCL 都源自同一创始突变事件，该事件可能早于现代犬种的建立。如果是这样，那么 CLN5 无义等位基因可能在其他尚未确定的品种中分离。因此，无论品种如何，出现类似 NCL 样症状的狗都应筛查这种 CLN5 无义等位基因。
