Homozygous PPT1 Splice Donor Mutation in a Cane Corso Dog With Neuronal Ceroid Lipofuscinosis

Abstract

A 10‐month‐old spayed female Cane Corso dog was evaluated after a 2‐month history of progressive blindness, ataxia, and lethargy. Neurologic examination abnormalities indicated a multifocal lesion with primarily cerebral and cerebellar signs. Clinical worsening resulted in humane euthanasia. On necropsy, there was marked astrogliosis throughout white matter tracts of the cerebrum, most prominently in the corpus callosum. In the cerebral cortex and midbrain, most neurons contained large amounts of autofluorescent storage material in the perinuclear area of the cells. Cerebellar storage material was present in the Purkinje cells, granular cell layer, and perinuclear regions of neurons in the deep nuclei. Neuronal ceroid lipofuscinosis (NCL) was diagnosed. Whole genome sequencing identified a PPT1c.124 + 1G>A splice donor mutation. This nonreference assembly allele was homozygous in the affected dog, has not previously been reported in dbSNP, and was absent from the whole genome sequences of 45 control dogs and 31 unaffected Cane Corsos. Our findings indicate a novel mutation causing the CLN1 form of NCL in a previously unreported dog breed. A canine model for CLN1 disease could provide an opportunity for therapeutic advancement, benefiting both humans and dogs with this disorder.

Canine neuronal ceroid lipofuscinoses: Promising models for preclinical testing of therapeutic interventions

“…1 and 2) (Kolicheski et al, 2017b). Although the ultrastructural appearances of the storage material in brain and retina were somewhat similar to those of other canine NCLs (Ashwini et al, 2016; Gilliam et al, 2015; Guo et al, 2014; Guo et al, 2015; Katz et al, 2011; Kolicheski et al, 2017a; Kolicheski et al, 2016; Kolicheski et al, 2017b; Sanders et al, 2010), the histological appearance of the storage material in the affected Shiba Inu heart was quite distinct from that of other NCLs in which heart histopathology had been examined (Figs. 3 and 4).…”

“…This approach enables one to screen a dog for candidate mutations in all of the known NCL genes at once with the added advantage of enabling one to search for candidate disease causing mutations in other genes if an affected dog does not have a mutation in one of the known NCL genes. To date, the mutations responsible for NCL have been discovered in Australian Cattle Dogs, Golden Retrievers, Chinese Crested dogs, Chihuahuas, Cane Corsos, and Alpenlandische Dachsbrackes using the whole genome sequencing approach (Faller et al, 2016; Gilliam et al, 2015; Guo et al, 2015; Hirz et al, 2016; Kolicheski et al, 2017a; Kolicheski et al, 2016). In total to date, 12 mutations in eight genes have been identified as causative for NCL in dogs (Table 1).…”

ATP13A2 missense variant in Australian Cattle Dogs with late onset neuronal ceroid lipofuscinosis

“…These cells may be microglia-derived phagocytic cells (gitter cells) that have taken up large amounts of storage material that originated in Purkinje cells that have degenerated. Non-Purkinje cells in or near the Purkinje cell layer that contain disease-related storage material have been reported in other forms of canine NCL [ 6 , 18 ], and a similar clustering of these cells in the Purkinje layer of the cerebellum occurs in at least one of these other NCLs [ 6 ]. Whether these cells represent phagocytic cells that have taken up storage material originally generated in Purkinje cells remains to be determined.…”

Neuronal ceroid lipofuscinosis in Salukis is caused by a single base pair insertion in CLN8

“…; Kolicheski et al . ). Time of onset in English Setters, Chihuahuas, American Bulldogs, Golden Retrievers, Border Collies and Australian Shepherds is around 12–18 months (Koppang ; Lingaas et al .…”