Mutational analysis of the feline CLN3 gene and an ultrastructural evaluation of lysosomal storage materials in a cat with neuronal ceroid lipofuscinosis: An investigation into the molecular basis of the disease

Furusawa, Yu; Mizukami, Keijiro; Yabuki, Akira; Kuwamura, Mitsuru; Chang, Hye-Sook; Hossain, Mohammad Arif; Rahman, Md. Mahfuzur; Uddin, Mohammad M.; Mitani, Sawane; Yamato, Osamu

doi:10.1016/j.tvjl.2012.04.025

Cited by 7 publications

(15 citation statements)

References 7 publications

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“…Although not pathognomonic for the disease, the identification on MRI of cerebral and cerebellar atrophy with widened cerebral sulci, cerebellar folia, and increased volume in the ventricular system further increases the antemortem suspicion. Similar clinical and imaging findings have been reported in cats . Because the clinical signs and the imaging findings can overlap with other lysosomal storage diseases, identification of accumulation of autofluorescent ceroid storage material in neurological tissues is required for confirmation .…”

Section: Introductionsupporting

confidence: 56%

“…The clinical features of 8 cats with NCL confirmed by histopathology have been reported since 1974 . Domestic shorthair (7/9) cats and Siamese (2/9) are the 2 reported breeds.…”

Section: Discussionmentioning

confidence: 98%

“…The NCLs also have been reported in dogs but only rarely in cats . So far, causative genetic variants in dogs are known for CLN1, 2, 5, 6, 7, 8, 10, and 12, whereas none have been reported in cats.…”

Section: Introductionmentioning

confidence: 99%

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A major facilitator superfamily domain 8 frameshift variant in a cat with suspected neuronal ceroid lipofuscinosis

Guevar

Hug

Giebels

et al. 2019

Veterinary Internal Medicne

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A 2-year-old male domestic shorthair cat was presented for a progressive history of abnormal posture, behavior, and mentation. Menace response was absent bilaterally, and generalized tremors were identified on neurological examination. A neuroanatomical diagnosis of diffuse brain dysfunction was made. A neurodegenerative disorder was suspected. Magnetic resonance imaging findings further supported the clinical suspicion. Whole-genome sequencing of the affected cat with filtering of variants against a database of unaffected cats was performed. Candidate variants were confirmed by Sanger sequencing followed by genotyping of a control population.Two homozygous private (unique to individual or families and therefore absent from the breed-matched controlled population) protein-changing variants in the major facilitator superfamily domain 8 (MFSD8) gene, a known candidate gene for neuronal ceroid lipofuscinosis type 7 (CLN7), were identified. The affected cat was homozygous for the alternative allele at both variants. This is the first report of a pathogenic alteration of the MFSD8 gene in a cat strongly suspected to have CLN7.

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Section: Introductionsupporting

confidence: 56%

“…The clinical features of 8 cats with NCL confirmed by histopathology have been reported since 1974 . Domestic shorthair (7/9) cats and Siamese (2/9) are the 2 reported breeds.…”

Section: Discussionmentioning

confidence: 98%

See 1 more Smart Citation

A major facilitator superfamily domain 8 frameshift variant in a cat with suspected neuronal ceroid lipofuscinosis

Guevar

Hug

Giebels

et al. 2019

Veterinary Internal Medicne

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show abstract

“…A number of cases of NCL have been reported in domestic cats based on clinical signs and pathology ( Nakayama et al 1993 ; Bildfell et al 1995 ; Weissenböck and Rossel 1997 ; Kuwamura et al 2009 ; Furusawa et al 2012 ; Chalkley et al 2014 ), but this is only the second case of feline NCL in which the underlying molecular genetic cause has been determined. In one previously reported case of NCL in a domestic short-haired cat, no candidate disease sequence variants were detected by targeted sequencing of the NCL genes PPT1 , CLN3 , CLN5 , CLN8 or CTSD ( Chalkley et al 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon inCLN6

Katz

Buckley²,

Biegen

et al. 2020

G3 Genes|Genomes|Genetics

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A neutered male domestic medium-haired cat presented at a veterinary neurology clinic at 20 months of age due to progressive neurological signs that included visual impairment, focal myoclonus, and frequent severe generalized seizures that were refractory to treatment with phenobarbital. Magnetic resonance imaging revealed diffuse global brain atrophy. Due to the severity and frequency of its seizures, the cat was euthanized at 22 months of age. Microscopic examination of the cerebellum, cerebral cortex and brainstem revealed pronounced intracellular accumulations of autofluorescent storage material and inflammation in all 3 brain regions. Ultrastructural examination of the storage material indicated that it consisted almost completely of tightly-packed membrane-like material. The clinical signs and neuropathology strongly suggested that the cat suffered from a form of neuronal ceroid lipofuscinosis (NCL). Whole exome sequence analysis was performed on genomic DNA from the affected cat. Comparison of the sequence data to whole exome sequence data from 39 unaffected cats and whole genome sequence data from an additional 195 unaffected cats revealed a homozygous variant in CLN6 that was unique to the affected cat. This variant was predicted to cause a stop gain in the transcript due to a guanine to adenine transition (ENSFCAT00000025909:c.668G>A; XM_003987007.5:c.668G>A) and was the sole loss of function variant detected. CLN6 variants in other species, including humans, dogs, and sheep, are associated with the CLN6 form of NCL. Based on the affected cat's clinical signs, neuropathology and molecular genetic analysis, we conclude that the cat's disorder resulted from the loss of function of CLN6. This study is only the second to identify the molecular genetic basis of a feline NCL. Other cats exhibiting similar signs can now be screened for the CLN6 variant. This could lead to establishment of a feline model of CLN6 disease that could be used in therapeutic intervention studies.

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“…The purpose of this study was to determine the proportion of transduced MNs all along the spinal cord and the profile of glial cell transduction in the whole CNS after intracisternal (IC) injection of self-complementary (sc) AAV9-CMV (cytomegalovirus)-GFP (green fluorescent protein) vectors in both neonatal and young cats, a large animal model in which different neurodegenerative diseases 22, 23, 24, 25, 26 and MN degeneration 27 have been described. Our results showed that scAAV9 injected in the CSF transduced the vast majority of MNs all along the spinal cord (84±5% in the cervical, 99±1% in the lumbar), whatever the age at the times of injection, with a limited off-target biodistribution of the vector.…”

Section: Introductionmentioning

confidence: 99%

Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats

et al. 2014

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Systemic and intracerebrospinal fluid delivery of adeno-associated virus serotype 9 (AAV9) has been shown to achieve widespread gene delivery to the central nervous system (CNS). However, after systemic injection, the neurotropism of the vector has been reported to vary according to age at injection, with greater neuronal transduction in newborns and preferential glial cell tropism in adults. This difference has not yet been reported after cerebrospinal fluid (CSF) delivery. The present study analyzed both neuronal and glial cell transduction in the CNS of cats according to age of AAV9 CSF injection. In both newborns and young cats, administration of AAV9-GFP in the cisterna magna resulted in high levels of motor neurons (MNs) transduction from the cervical (84±5%) to the lumbar (99±1%) spinal cord, demonstrating that the remarkable tropism of AAV9 for MNs is not affected by age at CSF delivery. Surprisingly, numerous oligodendrocytes were also transduced in the brain and in the spinal cord white matter of young cats, but not of neonates, indicating that (i) age of CSF delivery influences the tropism of AAV9 for glial cells and (ii) AAV9 intracisternal delivery could be relevant for both the treatment of MN and demyelinating disorders.

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Mutational analysis of the feline CLN3 gene and an ultrastructural evaluation of lysosomal storage materials in a cat with neuronal ceroid lipofuscinosis: An investigation into the molecular basis of the disease

Cited by 7 publications

References 7 publications

A major facilitator superfamily domain 8 frameshift variant in a cat with suspected neuronal ceroid lipofuscinosis

A major facilitator superfamily domain 8 frameshift variant in a cat with suspected neuronal ceroid lipofuscinosis

Neuronal Ceroid Lipofuscinosis in a Domestic Cat Associated with a DNA Sequence Variant That Creates a Premature Stop Codon inCLN6

Intracisternal delivery of AAV9 results in oligodendrocyte and motor neuron transduction in the whole central nervous system of cats

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