The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

Faller, Kiterie M E; Brás, José; Sharpe, S.; Anderson, Glenn; Darwent, Lee; Kun‐Rodrigues, Célia; Alroy, Joseph; Penderis, Jacques; Mole, Sara; Gutierrez‐Quintana, Rodrigo; Guerreiro, Rita

doi:10.1002/jnr.23710

Cited by 28 publications

(32 citation statements)

References 32 publications

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“…22 Similarly, another morphologic analysis of the retina from a patient with CLN7 carrying the intronic c.754þ2T>A mutation also showed a marked neuronal degeneration in all retinal layers with maximal neuronal loss in the ganglion cell layer. 15 Different from the observations in these patients with CLN7 22 and a CLN7 canine model, 46 we found no evidence for a neuronal depletion of the inner nuclear layer and the ganglion cell layer of Cln7 KO mice up to the age of 4 months. However, accumulation of storage material and elevated expression levels of various lysosomal proteins in CLN7-deficient retinas were particularly evident in the ganglion cell layer, indicative of a major lysosomal dysfunction in retinal ganglion cells.…”

Section: Discussioncontrasting

confidence: 56%

“…Retinal degeneration leading to visual impairment and ultimately blindness during the course of the disease has been reported as a typical neurologic symptom in patients with CLN7 with vLINCL phenotype, 7,8,[15][16][17][18][19]21,22,45 in a naturally occurring CLN7 canine model, 46 and in a hypomorphic mouse model of CLN7 disease. 11 However, precise information about the onset and progression of the retinal pathology, the affected retinal layers and retinal cell types, and the biochemical alterations associated with CLN7 disease, vLINCL phenotype, are largely missing.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, neuronal loss in the ganglion cell layer was detected at end stages of the disease both in patients with CLN7 22 and the CLN7 canine model. 46 In summary, this study provides the first comprehensive characterization of the retinal phenotype of a mouse model of CLN7 disease, vLINCL phenotype. Our results identify an early onset and rapidly progressing degeneration of rod photoreceptor cells as a major neurologic phenotype in CLN7-deficient mice.…”

Section: Discussionmentioning

confidence: 99%

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Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak

Brandenstein

Dulz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Neuronal ceroid lipofuscinoses comprise a genetically heterogeneous group of mainly childhood-onset neurodegenerative lysosomal storage disorders. Progressive loss of vision is among the typical clinical symptoms of these fatal disorders. Here, we performed a detailed analysis of retinal degeneration in mice deficient in the lysosomal membrane protein CLN7, a novel animal model of CLN7 disease.METHODS. Immunohistochemical analyses of retinas at different ages were performed to qualitatively and quantitatively characterize retinal degeneration in CLN7-deficient mice. Storage material in mutant retinas was analyzed by electron microscopy, and expression levels of various lysosomal proteins were studied using immunohistochemistry, immunoblot analyses, and quantitative real-time PCR.RESULTS. We observed an early onset and rapidly progressing degeneration of photoreceptor cells in CLN7-deficient mice, resulting in the loss of more than 70% rod photoreceptors in 4-month-old animals. The number of cone photoreceptors was not detectably altered at this age. Loss of rod photoreceptors was accompanied by reactive astrogliosis and microgliosis. Immunohistochemical and immunoblot analyses revealed accumulation of subunit c of mitochondrial ATP synthase and saposin D in mutant retinas, and electron microscopic analyses demonstrated the presence of curvilinear bodies or fingerprint-like profiles in various cell types of CLN7-deficient retinas. We also found a marked dysregulation of various lysosomal proteins in mutant retinas. CONCLUSIONS.We conclude that the retina of CLN7-deficient mice represents a useful model to elucidate the pathomechanisms ultimately leading to neurodegeneration in CLN7 disease, and to evaluate the efficacy of strategies aimed at developing treatments for this fatal neurodegenerative lysosomal storage disorder.

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Section: Discussioncontrasting

confidence: 56%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Jankowiak

Brandenstein

Dulz

et al. 2016

Invest. Ophthalmol. Vis. Sci.

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“…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).…”

Section: Canine Ncls With Known Causative Mutationsmentioning

confidence: 99%

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

Katz

Rustad²,

Robinson

et al. 2017

Neurobiology of Disease

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The neuronal ceroid lipofuscinoses (NCLs) are devastating inherited progressive neurodegenerative diseases, with most forms having a childhood onset of clinical signs. The NCLs are characterized by progressive cognitive and motor decline, vision loss, seizures, respiratory and swallowing impairment, and ultimately premature death. Different forms of NCL result from mutations in at least 13 genes. The clinical signs of some forms overlap significantly, so genetic testing is the only way to definitively determine which form an individual patient suffers from. At present, an effective treatment is available for only one form of NCL. Evidence of NCL has been documented in over 20 canine breeds and in mixed-breed dogs. To date, 12 mutations in 8 different genes orthologous to the human NCL genes have been found to underlie NCL in a variety of dog breeds. A Dachshund model with a null mutation in one of these genes is being utilized to investigate potential therapeutic interventions, including enzyme replacement and gene therapies. Demonstration of the efficacy of enzyme replacement therapy in this model led to successful completion of human clinical trials of this treatment. Further research into the other canine NCLs, with in-depth characterization and understanding of the disease processes, will likely lead to the development of successful therapeutic interventions for additional forms of NCL, for both human patients and animals with these disorders.

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“…To identify the molecular genetic cause of this Cane Corso's disease, we used the dog's DNA to generate a whole genome sequence. This has proven to be an efficient strategy for identifying the mutations responsible for NCL . Procedures for DNA isolation, library preparation, sequence generation, and sequence analysis are provided in the Data S1.…”

Section: Sequence Variants In Neuronal Ceroid Lipofuscinosis‐associatmentioning

confidence: 99%

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

Kolicheski

Heller

Arnold

et al. 2016

Veterinary Internal Medicne

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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.

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The Chihuahua dog: A new animal model for neuronal ceroid lipofuscinosis CLN7 disease?

Cited by 28 publications

References 32 publications

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

Retinal Degeneration in Mice Deficient in the Lysosomal Membrane Protein CLN7

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

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

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