6 Studies of homogenous populations: CLN5 and CLN8

Ranta, Susanna; Savukoski, Minna; Santavuori, Pirkko; Haltia, Matti

doi:10.1016/s0065-2660(01)45007-3

Cited by 17 publications

(14 citation statements)

References 29 publications

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“…PAS stains sugars with adjacent hydroxyl groups, and in this case, what are stained are most likely glycoproteins and/or oligosaccharyl dolichols ( Wisniewski et al 1988 ; Elleder 1989 ; Elleder et al 1989 ; Wisniewski and Maslinska 1990 ). LFB has been shown to stain the storage bodies that accumulate in cells in the NCLs ( Cho et al 1986 ; Weissenböck and Rossel 1997 ; Ranta et al 2001 ; Sinha et al 2004 ). The granule cell layer of the cerebellum was moderately depleted of cells and the cerebral cortex was thinner than normal.…”

Section: Resultsmentioning

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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Section: Resultsmentioning

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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“…In cases where the underlying mutation occurs in a gene orthologous to one of the human NCL genes, the major stored proteins have been found to be the same as in the corresponding human disorders. For example, NCL in English setters results from a mutation in the canine CLN8 gene, and the storage bodies contain large amounts of mitochondrial F 0 ATP synthase subunit c (Katz et al 1994(Katz et al , 2005a as they do in the corresponding human disorder (Herva et al 2000;Ranta et al 2001).…”

Section: Introductionmentioning

confidence: 99%

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

Katz

Sanders

Mooney

et al. 2007

J of Inher Metab Disea

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Summary The neuronal ceroid lipofuscinoses (NCLs) are inherited neurodegenerative diseases characterized by massive accumulation of autofluorescent storage bodies in neurons and other cells. A late‐onset form of NCL occurs in Tibetan terrier dogs. Gel electrophoretic analyses of isolated storage body proteins from brains of affected dogs indicated that a protein of approximately 50 kDa was consistently prominent and a 16 kDa component was present in some brain storage body preparations. Mass spectral analysis identified the 50 kDa protein as glial fibrillary acidic protein (GFAP), isoform 2. GFAP identification was supported by immunoblot and immunohistochemical analyses. Histone H4 was the major protein in the 16 kDa component. Specific accumulation of GFAP and histone H4 in storage bodies has not been previously reported for any of the NCLs. Tibetan terrier NCL may be the canine correlate of one of the human adult‐onset NCLs for which the genetic bases and storage body compositions have not yet been determined.

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“…The Finnish variant of late-infantile NCL (Finnish vLINCL or variant Jansky-Bielschowsky disease) is described in Finnish patients with onset at 2 to 7 years of age due to mutations in the CLN5 gene. The children are afflicted with problems in concentration, motor coordination, mental retardation, visual failure, ataxia, myoclonus and epilepsy [ 71 ]. The age at death varies considerably from 14 to 36 years [ 72 - 74 ].…”

Section: Cln5 (Finnish Variant Lincl)mentioning

confidence: 99%

“…It has the most protracted course of all the NCLs and is characterized by the onset of generalized seizures between 5 and 10 years of age and subsequent progressive mental retardation. Visual problems are not severe, myoclonus does not exist and the clinical progression of the disease is much slower [ 71 , 91 ].…”

Section: Cln8 (Epmr/northern Epilepsy)mentioning

confidence: 99%

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Analysis of NCL Proteins from an Evolutionary Standpoint

Muzaffar¹,

Pearce²

2008

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Abstract:The Neuronal Ceroid Lipofuscinoses (NCLs) are the most common group of neurodegenerative disorders of childhood. While mutations in eight different genes have been shown to be responsible for these clinically distinct types of NCL, the NCLs share many clinical and pathological similarities. We have conducted an exhaustive Basic Local Alignment Search Tool (BLAST) analysis of the human protein sequences for each of the eight known NCL proteins-CLN1, CLN2, CLN3, CLN5, CLN6, CLN7, CLN8 and CLN10. The number of homologous species per CLN-protein identified by BLAST searches varies depending on the parameters set for the BLAST search. For example, a lower threshold is able to pull up more homologous sequences whereas a higher threshold decreases this number. Nevertheless, the clade confines are consistent despite this variation in BLAST searching parameters. Further phylogenetic analyses on the appearance of NCL proteins through evolution reveals a different time line for the appearance of the CLN-proteins. Moreover, divergence of each protein shows a different pattern, providing important clues on the evolving role of these proteins. We present and review in-depth bioinformatic analysis of the NCL proteins and classify the CLN-proteins into families based on their structures and evolutionary relationships, respectively. Based on these analyses, we have grouped the CLN-proteins into common clades indicating a common evolving pathway within the evolutionary tree of life. CLN2 is grouped in Eubacteria, CLN1 and CLN10 in Viridiplantae, CLN3 in Fungi/ Metazoa, CLN7 in Bilateria and CLN5, CLN6 and CLN8 in Euteleostomi.

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6 Studies of homogenous populations: CLN5 and CLN8

Cited by 17 publications

References 29 publications

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

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

Accumulation of glial fibrillary acidic protein and histone H4 in brain storage bodies of Tibetan terriers with hereditary neuronal ceroid lipofuscinosis

Analysis of NCL Proteins from an Evolutionary Standpoint

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