p.Asn77Lys homozygous CLN6 mutation in two unrelated Japanese patients with Kufs disease, an adult onset neuronal ceroid lipofuscinosis

Onodera, Misaki; Tsujimoto, Saori; Doi, Syusuke; Yamashita, Arisa; Yamazaki, Tetsuo; Makifuchi, Takao; Inazu, Toshiyuki

doi:10.1016/j.cca.2021.09.021

Cited by 2 publications

(2 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Numerous pathogenic mutations in CLN6 have been reported in human subjects suffering from NCL [14,[36][37][38][39][40][41][42][43][44]. Among these are splice site variants in introns 2 and 4 and missense variants in all 7 exons [36,37,45].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinosis in a Mixed Breed Dog with a Splice Site Variant in CLN6

Mhlanga-Mutangadura,

Bullock,

Cerda-Gonzalez

et al. 2024

Preprint

View full text Add to dashboard Cite

A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors, seizure activity, ataxia, and pronounced visual impairment. The clinical signs were accompanied by global brain atrophy. Due to progression in the severity of disease signs, the dog was euthanized at 26 months of age. Examination of tissues collected at necropsy revealed dramatic intracellular accumulations of autofluorescent inclusions in the brain, retina, and cardiac muscle. The inclusions were immunopositive for subunit c of mitochondrial ATP synthase, and their ultrastructural appearances were similar to those of lysosomal storage bodies that accumulate in some of the neuronal ceroid lipofuscinosis (NCL) diseases. The also dog exhibited widespread neuroinflammation. Based on these findings, the dog was deemed likely to have suffered from a form of NCL. A whole genome sequence analysis of the proband’s DNA revealed a homozygous C to T substitution that altered the intron 3 – exon 4 splice site of CLN6. Other mutations in CLN6 cause NCL diseases in humans and animals including dogs. CLN6 protein was undetectable with immunolabeling in the tissues of the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the disorder in this dog is classified as an NCL resulting from the absence of CLN6 protein. Screening the dog’s genome for a panel of breed-specific polymorphisms indicated that its ancestry included numerous breeds, with no single breed predominating. This suggests that the CLN6 disease variant is likely to be present in other mixed breed dogs and at least some of the ancestral breeds.

show abstract

Section: Discussionmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinosis in a Mixed Breed Dog with a Splice Site Variant in CLN6

Mhlanga-Mutangadura,

Bullock,

Cerda-Gonzalez

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Numerous pathogenic mutations in CLN6 have been reported in human subjects suffering from NCL [ 14 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. Among these are splice site variants in introns 2 and 4 and missense variants in all seven exons [ 36 , 37 , 45 ].…”

Section: Discussionmentioning

confidence: 99%

Neuronal Ceroid Lipofuscinosis in a Mixed-Breed Dog with a Splice Site Variant in CLN6

Mhlanga-Mutangadura,

Bullock,

Cerda-Gonzalez

et al. 2024

Genes

View full text Add to dashboard Cite

A 23-month-old neutered male dog of unknown ancestry presented with a history of progressive neurological signs that included anxiety, cognitive impairment, tremors, seizure activity, ataxia, and pronounced visual impairment. The clinical signs were accompanied by global brain atrophy. Due to progression in the severity of disease signs, the dog was euthanized at 26 months of age. An examination of the tissues collected at necropsy revealed dramatic intracellular accumulations of autofluorescent inclusions in the brain, retina, and cardiac muscle. The inclusions were immunopositive for subunit c of mitochondrial ATP synthase, and their ultrastructural appearances were similar to those of lysosomal storage bodies that accumulate in some neuronal ceroid lipofuscinosis (NCL) diseases. The dog also exhibited widespread neuroinflammation. Based on these findings, the dog was deemed likely to have suffered from a form of NCL. A whole genome sequence analysis of the proband’s DNA revealed a homozygous C to T substitution that altered the intron 3–exon 4 splice site of CLN6. Other mutations in CLN6 cause NCL diseases in humans and animals, including dogs. The CLN6 protein was undetectable with immunolabeling in the tissues of the proband. Based on the clinical history, fluorescence and electron-microscopy, immunohistochemistry, and molecular genetic findings, the disorder in this dog was classified as an NCL resulting from the absence of the CLN6 protein. Screening the dog’s genome for a panel of breed-specific polymorphisms indicated that its ancestry included numerous breeds, with no single breed predominating. This suggests that the CLN6 disease variant is likely to be present in other mixed-breed dogs and at least some ancestral breeds, although it is likely to be rare since other cases have not been reported to date.

show abstract

p.Asn77Lys homozygous CLN6 mutation in two unrelated Japanese patients with Kufs disease, an adult onset neuronal ceroid lipofuscinosis

Cited by 2 publications

References 21 publications

Neuronal Ceroid Lipofuscinosis in a Mixed Breed Dog with a Splice Site Variant in CLN6

Neuronal Ceroid Lipofuscinosis in a Mixed Breed Dog with a Splice Site Variant in CLN6

Neuronal Ceroid Lipofuscinosis in a Mixed-Breed Dog with a Splice Site Variant in CLN6

Contact Info

Product

Resources

About