scholarly journals KIF1Bβ mutations detected in hereditary neuropathy impair IGF1R transport and axon growth

2018 ◽  
Vol 217 (10) ◽  
pp. 3480-3496 ◽  
Author(s):  
Fang Xu ◽  
Hironori Takahashi ◽  
Yosuke Tanaka ◽  
Sotaro Ichinose ◽  
Shinsuke Niwa ◽  
...  
Keyword(s):  
Neuronal Development ◽  
Binding Capacity ◽  
Axon Growth ◽  
Hereditary Neuropathy ◽  
Binding Partner ◽  
Charcot Marie Tooth Disease ◽  
Direct Binding ◽  
And Function ◽  
Igf1r Expression ◽  
Tooth Disease

KIF1Bβ is a kinesin-3 family anterograde motor protein essential for neuronal development, viability, and function. KIF1Bβ mutations have previously been reported in a limited number of pedigrees of Charcot-Marie-Tooth disease type 2A (CMT2A) neuropathy. However, the gene responsible for CMT2A is still controversial, and the mechanism of pathogenesis remains elusive. In this study, we show that the receptor tyrosine kinase IGF1R is a new direct binding partner of KIF1Bβ, and its binding and transport is specifically impaired by the Y1087C mutation of KIF1Bβ, which we detected in hereditary neuropathic patients. The axonal outgrowth and IGF-I signaling of Kif1b−/− neurons were significantly impaired, consistent with decreased surface IGF1R expression. The complementary capacity of KIF1Bβ-Y1087C of these phenotypes was significantly impaired, but the binding capacity to synaptic vesicle precursors was not affected. These data have supported the relevance of KIF1Bβ in IGF1R transport, which may give new clue to the neuropathic pathogenesis.

scholarly journals Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network

2021 ◽  
Vol 22 (2) ◽  
pp. 914
Author(s):  
Katarzyna Binięda ◽  
Weronika Rzepnikowska ◽  
Damian Kolakowski ◽  
Joanna Kaminska ◽  
Andrzej Antoni Szczepankiewicz ◽  
...  
Keyword(s):  
Golgi Apparatus ◽  
Experimental Therapy ◽  
Negative Effects ◽  
Gene Encoding ◽  
Charcot Marie Tooth Disease ◽  
Terra Incognita ◽  
And Function ◽  
Golgi Network ◽  
Cell Phenotypes ◽  
Tooth Disease

Charcot-Marie-Tooth disease (CMT) is a heritable neurodegenerative disease that displays great genetic heterogeneity. The genes and mutations that underlie this heterogeneity have been extensively characterized by molecular genetics. However, the molecular pathogenesis of the vast majority of CMT subtypes remains terra incognita. Any attempts to perform experimental therapy for CMT disease are limited by a lack of understanding of the pathogenesis at a molecular level. In this study, we aim to identify the molecular pathways that are disturbed by mutations in the gene encoding GDAP1 using both yeast and human cell, based models of CMT-GDAP1 disease. We found that some mutations in GDAP1 led to a reduced expression of the GDAP1 protein and resulted in a selective disruption of the Golgi apparatus. These structural alterations are accompanied by functional disturbances within the Golgi. We screened over 1500 drugs that are available on the market using our yeast-based CMT-GDAP1 model. Drugs were identified that had both positive and negative effects on cell phenotypes. To the best of our knowledge, this study is the first report of the Golgi apparatus playing a role in the pathology of CMT disorders. The drugs we identified, using our yeast-based CMT-GDAP1 model, may be further used in translational research.

scholarly journals Prevalence and characterization of pain in patients with Charcot-Marie-Tooth disease type 1A

2021 ◽  
Author(s):  
Helen AZEVEDO ◽  
Henrique COSTA ◽  
Eduardo DAVIDOVICH ◽  
Camila PUPE ◽  
Osvaldo José Moreira NASCIMENTO
Keyword(s):  
Neuropathic Pain ◽  
Clinical Evaluation ◽  
Disease Type ◽  
Moderate Intensity ◽  
Hereditary Neuropathy ◽  
Charcot Marie Tooth ◽  
Clinical Criteria ◽  
Charcot Marie Tooth Disease ◽  
Sf 36 ◽  
Tooth Disease

ABSTRACT Background: Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common form of hereditary neuropathy. Objective: To investigate the prevalence and characteristics of pain in patients with CMT1A. Methods: Nineteen patients with a diagnosis of CMT1A were evaluated between September 2018 and October 2019, and other causes of neuropathy were ruled out. The following tools were used for the pain assessment: neurological assessment, LANSS, DN4, clinical evaluation, VAS, CMTNS2 and SF-36. Statistical analysis was performed using prevalence analysis, t test, chi-square test and Spearman's rho. Results: The prevalence of pain was 84.2% in the sample of this study, with moderate intensity and nociceptive characteristics according to the LANSS scale (75%) and clinical evaluation (50%), but differing from DN4, which found neuropathic pain in the majority of the patients (56.2%). Mixed pain was also observed in 43.7% of the patients, according to clinical criteria. There was a statistically significant correlation between pain intensity and SF-36, thus demonstrating that the lower the pain was, the lower the impairment was, in all domains. Conclusion: Pain is a prevalent and important symptom in CMT1A, with moderate intensity and nociceptive characteristics according to two tools, but neuropathic pain is also present, and there may even be a mixed pattern of pain. The correlation of the pain with SF-36 suggests that pain relief could provide improvements to the quality of life of these individuals.

Quantitative measurement of duplicated DNA as a diagnostic test for Charcot-Marie-Tooth disease type 1a

1993 ◽  
Vol 39 (9) ◽  
pp. 1845-1849 ◽  
Author(s):  
G W Hensels ◽  
E A Janssen ◽  
J E Hoogendijk ◽  
L J Valentijn ◽  
F Baas ◽  
...  
Keyword(s):  
Preliminary Investigation ◽  
Sensory Neuropathy ◽  
Disease Type ◽  
Chromosome 17 ◽  
Hereditary Neuropathy ◽  
Chromosomal Dna ◽  
Gene Encoding ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Tooth Disease

Abstract Charcot-Marie-Tooth disease type 1 (CMT1) is a hereditary motor and sensory neuropathy. The autosomal dominant subtype is often linked with a large duplication on chromosome 17p11.2. The gene encoding the peripheral myelin protein PMP 22 (the critical gene in this subtype of CMT1) is located within this duplication. To detect this duplication in chromosomal DNA from individuals thought to have CMT1, we compared the hybridization signals of two DNA probes within this duplication (VAW412R3a and VAW409R3a) with the signal of a reference probe (E3.9). When duplication was present, the signals from the first two probes increased from 100% (for nonduplicated samples) to 145% and 142%, respectively. The day-to-day variance was 3.7% and 5.1%, respectively. We demonstrated this DNA duplication in 49 of 95 DNA samples from unrelated individuals thought to have CMT1. Moreover, because hereditary neuropathy with liability to pressure palsies (HNPP) is based on a DNA deletion in the same area of chromosome 17, this quantitative test may be useful in establishing the presence of HNPP. In a preliminary investigation, four unrelated patients with HNPP yielded test values of 63% and 54%, respectively, of those for nonduplicated samples (CV 19% and 18%, respectively; n = 4), suggesting a deletion in 17p11.2.

scholarly journals Genetic variation in Charcot–Marie–Tooth genes contributes to sensitivity to paclitaxel-induced peripheral neuropathy

2020 ◽  
Vol 21 (12) ◽  
pp. 841-851
Author(s):  
Yongzhen Chen ◽  
Fang Fang ◽  
Kelley M Kidwell ◽  
Kiran Vangipuram ◽  
Lauren A Marcath ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Additive Model ◽  
Systemic Exposure ◽  
The Other ◽  
Hereditary Neuropathy ◽  
Charcot Marie Tooth ◽  
Charcot Marie Tooth Disease ◽  
Genetic Predictors ◽  
Paclitaxel Treatment ◽  
Tooth Disease

Aim: This study explored whether inherited variants in genes causing the hereditary neuropathy condition Charcot–Marie–Tooth disease are associated with sensitivity to paclitaxel-induced peripheral neuropathy (PN). Patients & methods: Hereditary neuropathy genes previously associated with risk of paclitaxel-induced PN were sequenced in paclitaxel-treated patients. Eight putative genetic predictors in five hereditary neuropathy genes ( ARHGEF10, SBF2, FGD4, FZD3 and NXN) were tested for association with PN sensitivity after accounting for systemic exposure and clinical variables. Results: FZD3 rs7833751, a proxy for rs7001034, decreased PN sensitivity (additive model, β = -0.41; 95% CI: -0.66 to -0.17; p = 0.0011). None of the other genetic predictors were associated with PN sensitivity. Conclusion: Our results support prior evidence that FZD3 rs7001034 is protective of PN and may be useful for individualizing paclitaxel treatment to prevent PN.

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