Elevated peripheral myelin protein 22, reduced mitotic potential, and proteasome impairment in dermal fibroblasts from Charcot-Marie-Tooth disease type 1A patients.

Elevated peripheral myelin protein 22, reduced mitotic potential, and proteasome impairment in dermal fibroblasts from Charcot-Marie-Tooth disease type 1A patients. Am J Pathol. 2017 Dec 12;: Authors: Lee S, Bazick H, Chittoor-Vinod V, Al Salihi MO, Xia G, Notterpek L Abstract A common form of hereditary autosomal dominant demyelinating neuropathy known as Charcot-Marie-Tooth disease type 1A (CMT1A) is linked with duplication of the peripheral myelin protein 22 (PMP22) gene. Although studies from animal models have led to better understanding of the pathobiology of these neuropathies, there continues to be a gap in the translation of findings from rodents to humans. As PMP22 was originally identified in fibroblasts as growth arrest specific gene 3 (gas3) and is expressed broadly in the body, it was tested whether skin cells from neuropathic patients would display the cellular pathology observed in Schwann cells from rodent models. Dermal fibroblasts from two CMT1A pedigrees with confirmed PMP22 gene duplication were studied. Samples from age-matched non-neuropathic individuals were used as controls. CMT1A patient-derived cultures contain ∼1.5-fold elevated levels of PMP22 mRNA, exhibit reduced mitotic potential, and display intracellular protein aggregates as compared to cells from unaffected individuals. The presence of cytosolic PMP22 coincides with a decrease in proteasome activity and an increase in autophagy-lysosomal proteins, including LC3-II ...
Source: The American Journal of Pathology - Category: Pathology Authors: Tags: Am J Pathol Source Type: research

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Conclusion A novel GJB1 variant of c.-170T>G in non-coding region was found in this big Chinese CMTX1 pedigree. This is the first report of variant in non-coding DNA sequence associated with transient CNS symptoms. Thyroid malfunction may contribute to the CNS symptoms in this case. Ethics Statement This study has been reviewed and approved by the Ethics Committee of the China-Japan Union Hospital of Jilin University. Each member of the family provided written informed consent to the participation in the study, the genetic test, and authorized to publish the study including the photos in accordance with the Declarati...
Source: Frontiers in Neurology - Category: Neurology Source Type: research
Authors: Kanemaru K, Ogawa G, Mochizuki H, Nakazato M, Shiomi K Abstract A 33-year-old Japanese woman was referred for hoarseness. She had been diagnosed with Charcot-Marie-Tooth disease at age 3 and bilateral optic atrophy at age 15. Laryngoscopy revealed left vocal fold palsy. These findings suggested Charcot-Marie-Tooth disease type 2; the diagnosis was confirmed by a mitofusin 2 mutation analysis. Her symptoms remained stable for almost 10 years. Although vocal fold palsy and optic atrophy have been previously reported in patients with mitofusin 2 mutations, detailed clinical information and clinical course hav...
Source: Internal Medicine - Category: Internal Medicine Tags: Intern Med Source Type: research
Charcot-Marie-Tooth disease type 1A is the most common hereditary neuropathy. Affected individuals have a distal motor deficit, initially affecting the lower limbs and impairing walking performance. Isokinetic dynamometry can be used to objectively assess muscle strength of patients with neuromuscular disorders. No studies have evaluated the effect of muscle strength deficits of knee extensors and flexors on walking parameters for patients with Charcot-Marie-Tooth disease type 1A. The purpose of this study was to determine correlations between the isokinetic muscular strength of knee flexors and knee extensors and walk par...
Source: American Journal of Physical Medicine and Rehabilitation - Category: Rehabilitation Tags: Brief Reports Source Type: research
by Vera G. Volpi, Cinzia Ferri, Ilaria Fregno, Ubaldo Del Carro, Francesca Bianchi, Cristina Scapin, Emanuela Pettinato, Tatiana Solda, M. Laura Feltri, Maurizio Molinari, Lawrence Wrabetz, Maurizio D ’Antonio In the peripheral nervous system (PNS) myelinating Schwann cells synthesize large amounts of myelin protein zero (P0) glycoprotein, an abundant component of peripheral nerve myelin. In humans, mutations in P0 cause the demyelinating Charcot-Marie-Tooth 1B (CMT1B) neuropathy, one of the most diffus ed genetic disorders of the PNS. We previously showed that several mutations, such as the deletion of serine 63 (P...
Source: PLoS Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2, Published online: 17 April 2019; doi:10.1038/s41431-019-0403-8LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2
Source: European Journal of Human Genetics - Category: Genetics & Stem Cells Authors: Source Type: research
Conclusion: We conclude that elevated KB levels were beneficial for mitochondrial repair in the aging heart. However, an impaired MFN2-DRP1-mediated fusion-fission process in HF reduced this benefit, as well as Parkin degradation and mitophagic signaling cascade. Introduction The incidence of cardiovascular disease, including heart failure (HF), has increased steadily in the United States as the general population has aged (Roger et al., 2004; Savarese and Lund, 2017). Mitochondria are essential for energy generation to maintain cardiac contraction during each heartbeat. However, mitochondrial function decli...
Source: Frontiers in Physiology - Category: Physiology Source Type: research
(Cedars-Sinai Medical Center) A new study provides critical insight into a little-known, yet relatively common, inherited neurological condition called Charcot-Marie-Tooth disease. The findings point to a pathway to possible treatments for this disease and better understanding of other neurodegenerative disorders, including Alzheimer's disease, that affect millions.
Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
Aminoacyl-tRNA synthetases (ARSs) catalyze the attachment of specific amino acids to cognate tRNAs for use in protein synthesis. This historical function of ARSs and tRNAs is fairly well understood. However, ARSs and tRNAs also perform noncanonical functions that are continuing to be unveiled at a rapid pace. The expanded functions of these essential molecules of life range from roles in retroviral replication to stimulation of mammalian target of rapamycin (mTOR) activity; DNA repair, splicing, and transcriptional and translational regulation; and other aspects of cellular homeostasis. Furthermore, mutations in tRNAs and ...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: JBC Reviews Source Type: research
Aminoacyl-tRNA synthetases (aaRSs) are essential enzymes that catalyze the first reaction in protein biosynthesis, namely the charging of transfer RNAs (tRNAs) with their cognate amino acids. aaRSs have been increasingly implicated in dominantly and recessively inherited human diseases. The most common aaRS-associated monogenic disorder is the incurable neurodegenerative disease Charcot–Marie–Tooth neuropathy (CMT), caused by dominant mono-allelic mutations in aaRSs. With six currently known members (GlyRS, TyrRS, AlaRS, HisRS, TrpRS, and MetRS), aaRSs represent the largest protein family implicated in CMT etio...
Source: Journal of Biological Chemistry - Category: Chemistry Authors: Tags: JBC Reviews Source Type: research
Publication date: Available online 1 April 2019Source: Neurología (English Edition)Author(s): F.J. Domínguez Díez, J.T. López Alburquerque
Source: Neurologia - Category: Neurology Source Type: research
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