Lysine methylation of mitochondrial ATP synthase subunit c stored in tissues of dogs with hereditary ceroid lipofuscinosis

Katz, Martin L.; Christianson, J. Scott; Norbury, N. E.; Gao, Chun-Lan; Siakotos, A. N.; Koppang, N.

doi:10.1016/s0021-9258(17)36968-5

Cited by 40 publications

(8 citation statements)

References 19 publications

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“…In human and animal CLN6 disease, and in other forms of NCL, a major component of the storage material is the small subunit c protein of the inner mitochondrial membrane protein ATP synthase (Palmer et al 1989;Fearnley et al 1990;Ansari et al 1995;Kominami et al 1995;Tyynelä et al 1997;Umehara et al 1997;Jolly and Walkley 1999;Ranta et al 2001;Cook et al 2002;Cao et al 2011;Palmer et al 2013). This protein contains a trimethyl-lysine (TML) residue (Katz et al 1994;Katz 1996;Katz et al 1997;Chen et al 2004). TML is a precursor in the biosynthesis of carnitine, which plays an important role in fatty acid metabolism (Katz 1996;Adeva-Andany et al 2019).…”

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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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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“…Somewhat strikingly, almost all the human MTases described in previous sections were found to mediate methylation events originally identified in low-throughput studies, i.e. , those on NDUFS2, CS, ATPSc, ANT, and NDUFB3 ( 41 , 47 , 65 , 79 , 90 ). Common for these low-throughput studies is that they typically identified sites that contained more than one methyl group ( i.e.…”

Section: Discussionmentioning

confidence: 82%

“…In humans, three distinct genes ( ATP5MC1 , ATP5MC2 , and ATP5MC3 ) encode slightly different ATPSc precursors that give rise to an identical mature protein. Several independent reports showed that ATPSc is invariably trimethylated at Lys-43 (mature numbering) in metazoans ( 78 , 79 , 80 ).…”

Section: Mitochondrial Protein Methyltransferases and Their Targetsmentioning

confidence: 99%

Protein methylation in mitochondria

Małecki

Davydova

Falnes

2022

Journal of Biological Chemistry

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“…In various forms of NCL, including CLN5 disease, a major component of the lysosomal storage material is the subunit c protein of the mitochondrial membrane ATP synthase complex (Frugier et al., 2008; Ranta et al., 2001; Tyynelä et al., 1997). The subunit c protein contains two lysine residues, one of which is trimethylated, both in mitochondria and in the NCL‐specific storage bodies (Chen et al., 2004; Katz et al., 1994, 1995). In previous studies, it was found that plasma carnitine concentrations are low in the CLN8 form of canine NCL and in human subjects with the CLN3 form of NCL (Katz, 1996; Katz & Siakotos, 1995).…”

Section: Discussionmentioning

confidence: 99%

Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis

Meiman

Kick

Jensen

et al. 2022

Developmental Neurobiology

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Golden Retriever dogs with a frameshift variant in CLN5 (c.934_935delAG) suffer from a progressive neurodegenerative disorder analogous to the CLN5 form of neuronal ceroid lipofuscinosis (NCL). Five littermate puppies homozygous for the deletion allele were identified prior to the onset of disease signs. Studies were performed to characterize the onset and progression of the disease in these dogs. Neurological signs that included restlessness, unwillingness to cooperate with the handlers, and proprioceptive deficits first became apparent at approximately 12 months of age. The neurological signs progressed over time and by 21 to 23 months of age included general proprioceptive ataxia, menace response deficits, aggressive behaviors, cerebellar ataxia, intention tremors, decreased visual tracking, seizures, cognitive decline, and impaired prehension. Due to the severity of these signs, the dogs were euthanized between 21 and 23 months of age. Magnetic resonance imaging revealed pronounced progressive global brain atrophy with a more than sevenfold increase in the volume of the ventricular system between 9.5 and 22.5 months of age. Accompanying this atrophy were pronounced accumulations of autofluorescent inclusions throughout the brain and spinal cord. Ultrastructurally, the contents of these inclusions were found to consist primarily of membrane-like aggregates. Inclusions with similar fluorescence properties were present in cardiac muscle. Similar to other forms of NCL, the affected dogs had low plasma carnitine concentrations, suggesting impaired carnitine biosynthesis. These data on disease progression will be useful in future studies using the canine model for therapeutic intervention studies.

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Lysine methylation of mitochondrial ATP synthase subunit c stored in tissues of dogs with hereditary ceroid lipofuscinosis

Cited by 40 publications

References 19 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

Protein methylation in mitochondria

Characterization of neurological disease progression in a canine model of CLN5 neuronal ceroid lipofuscinosis

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