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Your search keyword '"Miers, Kathy E"' showing total 10 results
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10 results on '"Miers, Kathy E"'

1. Dominant NARS1 mutations causing axonal Charcot–Marie–Tooth disease expand NARS1-associated diseases

Author

Beijer, Danique, primary, Marte, Sheila, additional, Li, Jiaxin C, additional, De Ridder, Willem, additional, Chen, Jessie Z, additional, Tadenev, Abigail L D, additional, Miers, Kathy E, additional, Deconinck, Tine, additional, Macdonell, Richard, additional, Marques, Wilson, additional, De Jonghe, Peter, additional, Pratt, Samia L, additional, Meyer-Schuman, Rebecca, additional, Züchner, Stephan, additional, Antonellis, Anthony, additional, Burgess, Robert W, additional, and Baets, Jonathan, additional

Published
2024
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2. Precision mouse models of Yars/dominant intermediate Charcot-Marie-Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1

Author

Hines, Timothy J, Tadenev, Abigail L D, Lone, Museer A, Hatton, Courtney L, Bagasrawala, Inseyah, Stum, Morgane G, Miers, Kathy E, Hornemann, Thorsten, Burgess, Robert W, University of Zurich, and Burgess, Robert W

Subjects
1309 Developmental Biology, 1307 Cell Biology, 1105 Ecology, Evolution, Behavior and Systematics, 540 Chemistry, 1312 Molecular Biology, 610 Medicine & health, 2702 Anatomy, 2722 Histology, 10038 Institute of Clinical Chemistry
Published
2022

5. Precision mouse models of Yars/dominant intermediate Charcot‐Marie‐Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1.

Author

Hines, Timothy J., Tadenev, Abigail L. D., Lone, Museer A., Hatton, Courtney L., Bagasrawala, Inseyah, Stum, Morgane G., Miers, Kathy E., Hornemann, Thorsten, and Burgess, Robert W.

Subjects
TRANSFER RNA, CHARCOT-Marie-Tooth disease, LABORATORY mice, HUMAN genetics, MOTOR neuron diseases, NEUROPATHY, PERIPHERAL nervous system
Abstract

Animal models of neurodegenerative diseases such as inherited peripheral neuropathies sometimes accurately recreate the pathophysiology of the human disease, and sometimes accurately recreate the genetic perturbations found in patients. Ideally, models achieve both, but this is not always possible; nonetheless, such models are informative. Here we describe two animal models of inherited peripheral neuropathy: mice with a mutation in tyrosyl tRNA‐synthetase, YarsE196K, modeling dominant intermediate Charcot‐Marie‐Tooth disease type C (diCMTC), and mice with a mutation in serine palmitoyltransferase long chain 1, Sptlc1C133W, modeling hereditary sensory and autonomic neuropathy type 1 (HSAN1). YarsE196K mice develop disease‐relevant phenotypes including reduced motor performance and reduced nerve conduction velocities by 4 months of age. Peripheral motor axons are reduced in size, but there is no reduction in axon number and plasma neurofilament light chain levels are not increased. Unlike the dominant human mutations, the YarsE196K mice only show these phenotypes as homozygotes, or as compound heterozygotes with a null allele, and no phenotype is observed in E196K or null heterozygotes. The Sptlc1C133W mice carry a knockin allele and show the anticipated increase in 1‐deoxysphingolipids in circulation and in a variety of tissues. They also have mild behavioral defects consistent with HSAN1, but do not show neurophysiological defects or axon loss in peripheral nerves or in the epidermis of the hind paw or tail. Thus, despite the biochemical phenotype, the Sptlc1C133W mice do not show a strong neuropathy phenotype. Surprisingly, these mice were lethal as homozygotes, but the heterozygous genotype studied corresponds to the dominant genetics seen in humans. Thus, YarsE196K homozygous mice have a relevant phenotype, but imprecisely reproduce the human genetics, whereas the Sptlc1C133W mice precisely reproduce the human genetics, but do not recreate the disease phenotype. Despite these shortcomings, both models are informative and will be useful for future research. [ABSTRACT FROM AUTHOR]

Published
2022
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6. Genetic analysis of Pycr1 and Pycr2 in mice

Author

Stum, Morgane G, primary, Tadenev, Abigail L D, additional, Seburn, Kevin L, additional, Miers, Kathy E, additional, Poon, Pak P, additional, McMaster, Christopher R, additional, Robinson, Carolyn, additional, Kane, Coleen, additional, Silva, Kathleen A, additional, Cliften, Paul F, additional, Sundberg, John P, additional, Reinholdt, Laura G, additional, John, Simon W M, additional, and Burgess, Robert W, additional

Published
2021
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7. Metabolite profile of a mouse model of Charcot–Marie–Tooth type 2D neuropathy: implications for disease mechanisms and interventions

Author

Bais, Preeti, primary, Beebe, Kirk, additional, Morelli, Kathryn H., additional, Currie, Meagan E., additional, Norberg, Sara N., additional, Evsikov, Alexei V., additional, Miers, Kathy E., additional, Seburn, Kevin L., additional, Guergueltcheva, Velina, additional, Kremensky, Ivo, additional, Jordanova, Albena, additional, Bult, Carol J., additional, and Burgess, Robert W., additional

Published
2016
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10. Genetic analysis of Pycr1and Pycr2in mice

Author

Stum, Morgane G, Tadenev, Abigail L D, Seburn, Kevin L, Miers, Kathy E, Poon, Pak P, McMaster, Christopher R, Robinson, Carolyn, Kane, Coleen, Silva, Kathleen A, Cliften, Paul F, Sundberg, John P, Reinholdt, Laura G, John, Simon W M, and Burgess, Robert W

Abstract

The final step in proline biosynthesis is catalyzed by three pyrroline-5-carboxylate reductases, PYCR1, PYCR2, and PYCR3, which convert pyrroline-5-carboxylate (P5C) to proline. Mutations in human PYCR1and ALDH18A1(P5C Synthetase) cause Cutis Laxa (CL), whereas mutations in PYCR2cause hypomyelinating leukodystrophy 10 (HLD10). Here, we investigated the genetics of Pycr1 and Pycr2in mice. A null allele of Pycr1did not show integument or CL-related phenotypes. We also studied a novel chemically-induced mutation in Pycr2. Mice with recessive loss-of-function mutations in Pycr2showed phenotypes consistent with neurological and neuromuscular disorders, including weight loss, kyphosis, and hind-limb clasping. The peripheral nervous system was largely unaffected, with only mild axonal atrophy in peripheral nerves. A severe loss of subcutaneous fat in Pycr2 mutant mice is reminiscent of a CL-like phenotype, but primary features such as elastin abnormalities were not observed. Aged Pycr2mutant mice had reduced white blood cell counts and altered lipid metabolism, suggesting a generalized metabolic disorder. PYCR1 and -2 have similar enzymatic and cellular activities, and consistent with previous studies, both were localized in the mitochondria in fibroblasts. Both PYCR1and -2were able to complement the loss of Pro3, the yeast enzyme that converts P5C to proline, confirming their activity as P5C reductases. In mice, Pycr1; Pycr2double mutants were sub-viable and unhealthy compared to either single mutant, indicating the genes are largely functionally redundant. Proline levels were not reduced, and precursors were not increased in serum from Pycr2mutant mice or in lysates from skin fibroblast cultures, but placing Pycr2mutant mice on a proline-free diet worsened the phenotype. Thus, Pycr1and -2have redundant functions in proline biosynthesis, and their loss makes proline a semi-essential amino acid. These findings have implications for understanding the genetics of CL and HLD10, and for modeling these disorders in mice.

Published
2021
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