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1.
Anim Genet ; 2024 Jun 12.
Article in English | MEDLINE | ID: mdl-38866396

ABSTRACT

Neuronal ceroid lipofuscinosis (NCL) is a group of neurodegenerative disorders that occur in humans, dogs, and several other species. NCL is characterised clinically by progressive deterioration of cognitive and motor function, epileptic seizures, and visual impairment. Most forms present early in life and eventually lead to premature death. Typical pathological changes include neuronal accumulation of autofluorescent, periodic acid-Schiff- and Sudan black B-positive lipopigments, as well as marked loss of neurons in the central nervous system. Here, we describe a 19-month-old Schapendoes dog, where clinical signs were indicative of lysosomal storage disease, which was corroborated by pathological findings consistent with NCL. Whole genome sequencing of the affected dog and both parents, followed by variant calling and visual inspection of known NCL genes, identified a missense variant in CLN6 (c.386T>C). The variant is located in a highly conserved region of the gene and predicted to be harmful, which supports a causal relationship. The identification of this novel CLN6 variant enables pre-breeding DNA-testing to prevent future cases of NCL6 in the Schapendoes breed, and presents a potential natural model for NCL6 in humans.

2.
PLoS One ; 17(1): e0261845, 2022.
Article in English | MEDLINE | ID: mdl-35061740

ABSTRACT

A number of inherited ataxias is known in humans, with more than 250 loci implicated, most of which are included in human ataxia screening panels. Anecdotally, cases of ataxia in the Norwegian elkhound black have been known for the last 40 years. Affected puppies from three litters were clinically and neurologically examined, and postmortem samples were collected for morphological studies, including ultrastructural analyses. The puppies displayed vestibulocerebellar neurological signs and had degenerative histopathological alterations in cerebellum and brain stem. Three affected dogs, each from different litters, as well as both parents and one healthy littermate from each litter, were whole genome sequenced. Through variant calling we discovered a disease-associated 1 bp deletion in HACE1 (CFA12), resulting in a frameshift at codon 333 and a premature stop codon at codon 366. The perfect association combined with the predicted significant molecular effect, strongly suggest that we have found the causative mutation for Norwegian elkhound black ataxia. We have identified a novel candidate gene for ataxia where dogs can serve as a spontaneous model for improved understanding of ataxia, also in human.


Subject(s)
Ataxia/genetics , Base Sequence , Dog Diseases/genetics , Models, Genetic , Sequence Deletion , Ubiquitin-Protein Ligases/genetics , Animals , Ataxia/enzymology , Ataxia/pathology , Dog Diseases/enzymology , Dog Diseases/pathology , Dogs , Male , Ubiquitin-Protein Ligases/metabolism
3.
J Vet Intern Med ; 36(2): 672-678, 2022 Mar.
Article in English | MEDLINE | ID: mdl-35019187

ABSTRACT

BACKGROUND: Tongue atrophy with wrinkling as a clinical sign of inherited polyneuropathies has not been reported in dogs. OBJECTIVES: Clinically describe tongue atrophy as well as morphology of the tongue and hypoglossal nerve in Alaskan malamute polyneuropathy (AMPN). ANIMALS: Six client-owned Alaskan malamute dogs diagnosed with AMPN, all homozygous for the causative mutation in the N-myc downstream-regulated gene 1 (NDRG1) and 1 neurologically normal control Alaskan malamute. METHODS: Prospective case study. Clinical and neurological examinations were performed on affected dogs. Necropsy samples from the tongue muscle and hypoglossal nerve were examined by light and electron microscopy. RESULTS: All affected dogs had abnormal wrinkles and grooves on the dorsal surface of the tongue, a clinical sign not described previously in dogs with AMPN. Electromyography of the tongue performed in 2 dogs showed spontaneous activity. Five affected dogs underwent necropsy studies. Histopathology of the tongue showed groups of angular atrophic myofibers and changes in the hypoglossal nerve included thinly myelinated fibers, small onion bulbs, folded myelin, and axonal degeneration. CONCLUSION AND CLINICAL IMPORTANCE: Histopathologic changes in the tongue and hypoglossal nerve were consistent with previously reported changes in skeletal muscle and other nerves from dogs with AMPN. Therefore, we conclude that macroscopic tongue atrophy is part of the disease phenotype of AMPN and should be considered a potential clinical sign in dogs with polyneuropathies.


Subject(s)
Dog Diseases , Polyneuropathies , Animals , Atrophy/pathology , Atrophy/veterinary , Dog Diseases/diagnosis , Dog Diseases/genetics , Dog Diseases/pathology , Dogs , Mutation , Polyneuropathies/genetics , Polyneuropathies/pathology , Polyneuropathies/veterinary , Tongue/pathology
4.
Neuromuscul Disord ; 31(1): 56-68, 2021 01.
Article in English | MEDLINE | ID: mdl-33334662

ABSTRACT

Mutations in the N-myc downstream-regulated gene 1 (NDRG1) cause degenerative polyneuropathy in ways that are poorly understood. We have investigated Alaskan Malamute dogs with neuropathy caused by a missense mutation in NDRG1. In affected animals, nerve levels of NDRG1 protein were reduced by more than 70% (p< 0.03). Nerve fibers were thinly myelinated, loss of large myelinated fibers was pronounced and teased fiber preparations showed both demyelination and remyelination. Inclusions of filamentous material containing actin were present in adaxonal Schwann cell cytoplasm and Schmidt-Lanterman clefts. This condition strongly resembles the human Charcot-Marie-Tooth type 4D. However, the focally folded myelin with adaxonal infoldings segregating the axon found in this study are ultrastructural changes not described in the human disease. Furthermore, lipidomic analysis revealed a profound loss of peripheral nerve lipids. Our data suggest that the low levels of mutant NDRG1 is insufficient to support Schwann cells in maintaining myelin homeostasis.


Subject(s)
Cell Cycle Proteins , Charcot-Marie-Tooth Disease/veterinary , Dog Diseases/genetics , Intracellular Signaling Peptides and Proteins , Schwann Cells/metabolism , Animals , Charcot-Marie-Tooth Disease/genetics , Dogs , Female , Male , Mutation/genetics , Mutation, Missense , Myelin Sheath , Polyneuropathies/genetics
6.
FASEB J ; 34(2): 2359-2375, 2020 02.
Article in English | MEDLINE | ID: mdl-31907995

ABSTRACT

Studies in mice with ablation of Prnp, the gene that encodes the cellular prion protein (PrPC ), have led to the hypothesis that PrPC is important for peripheral nerve myelin maintenance. Here, we have used a nontransgenic animal model to put this idea to the test; namely, goats that, due to a naturally occurring nonsense mutation, lack PrPC . Teased nerve fiber preparation revealed a demyelinating pathology in goats without PrPC . Affected nerves were invaded by macrophages and T cells and displayed vacuolated fibers, shrunken axons, and onion bulbs. Peripheral nerve lipid composition was similar in young goats with or without PrPC , but markedly different between corresponding groups of adult goats, reflecting the progressive nature of the neuropathy. This is the first report of a subclinical demyelinating polyneuropathy caused by loss of PrPC function in a nontransgenic mammal.


Subject(s)
Demyelinating Diseases/immunology , Goats/immunology , Myelin Sheath/immunology , Polyneuropathies/immunology , PrPC Proteins/deficiency , Animals , Demyelinating Diseases/pathology , Macrophages/immunology , Macrophages/pathology , Mice , Myelin Sheath/pathology , Polyneuropathies/pathology , PrPC Proteins/immunology , T-Lymphocytes/immunology , T-Lymphocytes/pathology
7.
BMC Vet Res ; 15(1): 121, 2019 Apr 27.
Article in English | MEDLINE | ID: mdl-31029158

ABSTRACT

BACKGROUND: Mutations in the N-myc downstream-regulated gene 1 (NDRG1) can cause degenerative polyneuropathy in humans, dogs, and rodents. In humans, this motor and sensory neuropathy is known as Charcot-Marie-Tooth disease type 4D, and it is assumed that analogous canine diseases can be used as models for this disease. NDRG1 is also regarded as a metastasis-suppressor in several malignancies. The tissue distribution of NDRG1 has been described in humans and rodents, but this has not been studied in the dog. RESULTS: By immunolabeling and Western blotting, we present a detailed mapping of NDRG1 in dog tissues and primary canine Schwann cell cultures, with particular emphasis on peripheral nerves. High levels of phosphorylated NDRG1 appear in distinct subcellular localizations of the Schwann cells, suggesting signaling-driven rerouting of the protein. In a nerve from an Alaskan malamute homozygous for the disease-causing Gly98Val mutation in NDRG1, this signal was absent. Furthermore, NDRG1 is present in canine epithelial cells, predominantly in the cytosolic compartment, often with basolateral localization. Constitutive expression also occurs in mesenchymal cells, including developing spermatids that are transiently positive for NDRG1. In some cells, NDRG1 localize to centrosomes. CONCLUSIONS: Overall, canine NDRG1 shows a cell and context-dependent localization. Our data from peripheral nerves and primary Schwann cell cultures suggest that the subcellular localization of NDRG1 in Schwann cells is dynamically influenced by signaling events leading to reversible phosphorylation of the protein. We propose that disease-causing mutations in NDRG1 can disrupt signaling in myelinating Schwann cells, causing disturbance in myelin homeostasis and axonal-glial cross talk, thereby precipitating polyneuropathy.


Subject(s)
Cell Cycle Proteins/metabolism , Dog Diseases/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Polyneuropathies/veterinary , Schwann Cells/metabolism , Animals , Antibodies , Cell Cycle Proteins/genetics , Cells, Cultured , Dogs , Gene Expression Regulation , Intracellular Signaling Peptides and Proteins/genetics , Male , Mesenchymal Stem Cells , Mutation , Polyneuropathies/genetics , Polyneuropathies/metabolism , Protein Isoforms , Spermatids
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