VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy
Artículo Materias > Biomedicina Universidad Europea del Atlántico > Investigación > Artículos y libros Abierto Inglés Background Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous. Patient and methods In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole-exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein. Results A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C-terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild-type VRK1. Conclusion The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation. metadata Marcos, Ana T.; Martín‐Doncel, Elena; Morejón‐García, Patricia; Marcos‐Alcalde, Iñigo; Gómez‐Puertas, Paulino; Segura‐Puimedon, María; Armengol, Lluis; Navarro‐Pando, José M. y Lazo, Pedro A. mail SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, SIN ESPECIFICAR, jose.navarro@uneatlantico.es, SIN ESPECIFICAR (2020) VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. Annals of Clinical and Translational Neurology, 7 (5). pp. 808-818. ISSN 2328-9503
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Resumen
Background Distal motor neuropathies with a genetic origin have a heterogeneous clinical presentation with overlapping features affecting distal nerves and including spinal muscular atrophies and amyotrophic lateral sclerosis. This indicates that their genetic background is heterogeneous. Patient and methods In this work, we have identified and characterized the genetic and molecular base of a patient with a distal sensorimotor neuropathy of unknown origin. For this study, we performed whole-exome sequencing, molecular modelling, cloning and expression of mutant gene, and biochemical and cell biology analysis of the mutant protein. Results A novel homozygous recessive mutation in the human VRK1 gene, coding for a chromatin kinase, causing a substitution (c.637T > C; p.Tyr213His) in exon 8, was detected in a patient presenting since childhood a progressive distal sensorimotor neuropathy and spinal muscular atrophy syndrome, with normal intellectual development. Molecular modelling predicted this mutant VRK1 has altered the kinase activation loop by disrupting its interaction with the C-terminal regulatory region. The p.Y213H mutant protein has a reduced kinase activity with different substrates, including histones H3 and H2AX, proteins involved in DNA damage responses, such as p53 and 53BP1, and coilin, the scaffold for Cajal bodies. The mutant VRK1(Y213H) protein is unable to rescue the formation of Cajal bodies assembled on coilin, in the absence of wild-type VRK1. Conclusion The VRK1(Y213H) mutant protein alters the activation loop, impairs the kinase activity of VRK1 causing a functional insufficiency that impairs the formation of Cajal bodies assembled on coilin, a protein that regulates SMN1 and Cajal body formation.
| Tipo de Documento: | Artículo |
|---|---|
| Clasificación temática: | Materias > Biomedicina |
| Divisiones: | Universidad Europea del Atlántico > Investigación > Artículos y libros |
| Depositante: | Usuarios 0 no encontrado. |
| Depositado: | 01 Jun 2021 23:55 |
| Ultima Modificación: | 03 Jul 2023 23:30 |
| URI: | https://repositorio.uneatlantico.es/id/eprint/121 |
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- VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. (deposited 01 Jun 2021 23:55) [Mostrada Ahora]
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- Marcos, Ana T.; Martín‐Doncel, Elena; Morejón‐García, Patricia; Marcos‐Alcalde, Iñigo; Gómez‐Puertas, Paulino; Segura‐Puimedon, María; Armengol, Lluis; Navarro‐Pando, José M. y Lazo, Pedro A. VRK1 (Y213H) homozygous mutant impairs Cajal bodies in a hereditary case of distal motor neuropathy. (deposited 01 Jun 2021 23:55) [Mostrada Ahora]
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Introduction Cancer in older adults is often associated with functional limitations, geriatric syndromes, poor self-rated health, vulnerability, and frailty, and these conditions might worsen treatment-related side effects. Recent guidelines for patients with cancer during and after treatment have documented the beneficial effects of exercise to counteract certain side effects; however, little is known about the role of exercise during cancer treatment in older adults. Materials and Methods This is a multicentre randomised controlled trial in which 200 participants will be allocated to a control group or an intervention group (the sample size has been calculated to detect a clinical difference of 1 point in Short Physical Performance Battery (SPPB) score, assuming an α error of 0.05, a β error of 0.20, and a 10 % loss rate). Patients aged ≥70 years, diagnosed with any type of solid cancer and candidates for systemic treatment are eligible. Subjects in the intervention group are invited to participate in a 12-week supervised multicomponent exercise programme in addition to receiving usual care. Study assessments are conducted at baseline and three months. The primary outcome measure is physical function as assessed by the SPPB. Secondary outcome measures include comprehensive geriatric assessment scores (including social situation, basic and instrumental activities of daily living, cognitive function, depression, nutritional status, polypharmacy, geriatric syndromes, pain, and emotional distress), anthropometric characteristics, frailty status, physical fitness, physical activity, cognitive function, quality of life, fatigue, and nutritional status. Study assessments also include analysis of inflammatory, endocrine, and nutritional mediators in serum and plasma as potential frailty biomarkers at mRNA and protein levels and multiparametric flow cytometric analysis to measure immunosenescence markers on T and NK cells. Discussion This study seeks to extend our knowledge on exercise interventions during systemic anticancer treatment in patients over 70 years of age. Results from this research will guide the management of older adults during systemic treatment in hospitals seeking to enhance the standard of care.
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