Sign in to use this feature.

Years

Between: -

Subjects

remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline
remove_circle_outline

Journals

Article Types

Countries / Regions

Search Results (9)

Search Parameters:
Keywords = GDAP1 gene mutations

Order results
Result details
Results per page
Select all
Export citation of selected articles as:
14 pages, 710 KiB  
Review
A Role of Inflammation in Charcot–Marie–Tooth Disorders—In a Perspective of Treatment?
by Joanna Kamińska and Andrzej Kochański
Int. J. Mol. Sci. 2025, 26(1), 15; https://doi.org/10.3390/ijms26010015 - 24 Dec 2024
Cited by 2 | Viewed by 1269
Abstract
Despite the fact that there are published case reports and model work providing evidence of inflammation in Charcot–Marie–Tooth disorders (CMTs), in clinical practice, CMT and inflammatory neuropathies are always classified as two separate groups of disorders. This sharp separation of chronic neuropathies into [...] Read more.
Despite the fact that there are published case reports and model work providing evidence of inflammation in Charcot–Marie–Tooth disorders (CMTs), in clinical practice, CMT and inflammatory neuropathies are always classified as two separate groups of disorders. This sharp separation of chronic neuropathies into two groups has serious clinical implications. As a consequence, the patients harboring CMT mutations are practically excluded from pharmacological anti-inflammatory treatments. In this review, we present that neuropathological studies of peripheral nerves taken from some patients representing familial aggregation of CMTs revealed the presence of inflammation within the nerves. This shows that neurodegeneration resulting from germline mutations and the inflammatory process are not mutually exclusive. We also point to reports demonstrating that, at the clinical level, a positive response to anti-inflammatory therapy was observed in some patients diagnosed with CMTs, confirming the role of the inflammatory component in CMT. We narrowed a group of more than 100 genes whose mutations were found in CMT-affected patients to the seven most common (MPZ, PMP22, GJB1, SEPT9, LITAF, FIG4, and GDAP1) as being linked to the coexistence of hereditary and inflammatory neuropathy. We listed studies of mouse models supporting the idea of the presence of an inflammatory process in some CMTs and studies demonstrating at the cellular level the presence of an inflammatory response. In the following, we discuss the possible molecular basis of some neuropathies involving neurodegenerative and inflammatory processes at both the clinical and morphological levels. Finally, we discuss the prospect of a therapeutic approach using immunomodulation in some patients affected by CMTs. Full article
Show Figures

Figure 1

12 pages, 2999 KiB  
Article
Amlexanox: Readthrough Induction and Nonsense-Mediated mRNA Decay Inhibition in a Charcot–Marie–Tooth Model of hiPSCs-Derived Neuronal Cells Harboring a Nonsense Mutation in GDAP1 Gene
by Nesrine Benslimane, Federica Miressi, Camille Loret, Laurence Richard, Angélique Nizou, Ioanna Pyromali, Pierre-Antoine Faye, Frédéric Favreau, Fabrice Lejeune and Anne-Sophie Lia
Pharmaceuticals 2023, 16(7), 1034; https://doi.org/10.3390/ph16071034 - 21 Jul 2023
Cited by 7 | Viewed by 2623
Abstract
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system [...] Read more.
Nonsense mutations are involved in multiple peripheral neuropathies. These mutations induce the presence of a premature termination codon (PTC) at the mRNA level. As a result, a dysfunctional or truncated protein is synthesized, or even absent linked to nonsense-mediated mRNA degradation (NMD) system activation. Readthrough molecules or NMD inhibitors could be innovative therapies in these hereditary neuropathies, particularly molecules harboring the dual activity as amlexanox. Charcot–Marie–Tooth (CMT) is the most common inherited pathology of the peripheral nervous system, affecting 1 in 2500 people worldwide. Nonsense mutations in the GDAP1 gene have been associated with a severe form of CMT, prompting us to investigate the effect of readthrough and NMD inhibitor molecules. Although not clearly defined, GDAP1 could be involved in mitochondrial functions, such as mitophagy. We focused on the homozygous c.581C>G (p.Ser194*) mutation inducing CMT2H using patient human induced pluripotent stem cell (hiPSC)-derived neuronal cells. Treatment during 20 h with 100 µM of amlexanox on this cell model stabilized GDAP1 mRNAs carrying UGA-PTC and induced a restoration of the mitochondrial morphology. These results highlight the potential of readthrough molecules associated to NMD inhibitors for the treatment of genetic alterations in CMT, opening the way for future investigations and a potential therapy. Full article
(This article belongs to the Special Issue Recent Advances in the Pharmacology of Peripheral Neuropathy)
Show Figures

Graphical abstract

13 pages, 2172 KiB  
Article
The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?
by Dagmara Kabzińska, Katarzyna Chabros, Joanna Kamińska and Andrzej Kochański
Genes 2022, 13(9), 1546; https://doi.org/10.3390/genes13091546 - 27 Aug 2022
Cited by 4 | Viewed by 2024
Abstract
Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT [...] Read more.
Charcot–Marie–Tooth disorders (CMT) represent a highly heterogeneous group of diseases of the peripheral nervous system in which more than 100 genes are involved. In some CMT patients, a few weak sequence variants toward other CMT genes are detected instead of one leading CMT mutation. Thus, the presence of a few variants in different CMT-associated genes raises the question concerning the pathogenic status of one of them. In this study, we aimed to analyze the pathogenic effect of c.664G>A, p.Glu222Lys variant in the GDAP1 gene, whose mutations are known to be causative for CMT type 4A (CMT4A). Due to low penetrance and a rare occurrence limited to five patients from two Polish families affected by the CMT phenotype, there is doubt as to whether we are dealing with real pathogenic mutation. Thus, we aimed to study the pathogenic effect of the c.664G>A, p.Glu222Lys variant in its natural environment, i.e., the neuronal SH-SY5Y cell line. Additionally, we have checked the pathogenic status of p.Glu222Lys in the broader context of the whole exome. We also have analyzed the impact of GDAP1 gene mutations on the morphology of the transfected cells. Despite the use of several tests to determine the pathogenicity of the p.Glu222Lys variant, we cannot point to one that would definitively solve the problem of pathogenicity. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
Show Figures

Figure 1

14 pages, 885 KiB  
Article
Rare among Rare: Phenotypes of Uncommon CMT Genotypes
by Luca Gentile, Massimo Russo, Federica Taioli, Moreno Ferrarini, M’Hammed Aguennouz, Carmelo Rodolico, Antonio Toscano, Gian Maria Fabrizi and Anna Mazzeo
Brain Sci. 2021, 11(12), 1616; https://doi.org/10.3390/brainsci11121616 - 8 Dec 2021
Cited by 2 | Viewed by 3392
Abstract
(1) Background: Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other [...] Read more.
(1) Background: Charcot–Marie–Tooth disease (CMT) is the most frequent form of inherited chronic motor and sensory polyneuropathy. Over 100 CMT causative genes have been identified. Previous reports found PMP22, GJB1, MPZ, and MFN2 as the most frequently involved genes. Other genes, such as BSCL2, MORC2, HINT1, LITAF, GARS, and autosomal dominant GDAP1 are responsible for only a minority of CMT cases. (2) Methods: we present here our records of CMT patients harboring a mutation in one of these rare genes (BSCL2, MORC2, HINT1, LITAF, GARS, autosomal dominant GDAP1). We studied 17 patients from 8 unrelated families. All subjects underwent neurologic evaluation and genetic testing by next-generation sequencing on an Ion Torrent PGM (Thermo Fischer) with a 44-gene custom panel. (3) Results: the following variants were found: BSCL2 c.263A > G p.Asn88Ser (eight subjects), MORC2 c.1503A > T p.Gln501His (one subject), HINT1 c.110G > C p.Arg37Pro (one subject), LITAF c.404C > G p.Pro135Arg (two subjects), GARS c.1660G > A p.Asp554Asn (three subjects), GDAP1 c.374G > A p.Arg125Gln (two subjects). (4) Expanding the spectrum of CMT phenotypes is of high relevance, especially for less common variants that have a higher risk of remaining undiagnosed. The necessity of reaching a genetic definition for most patients is great, potentially making them eligible for future experimentations. Full article
(This article belongs to the Section Molecular and Cellular Neuroscience)
Show Figures

Figure A1

19 pages, 11871 KiB  
Article
GDAP1 Involvement in Mitochondrial Function and Oxidative Stress, Investigated in a Charcot-Marie-Tooth Model of hiPSCs-Derived Motor Neurons
by Federica Miressi, Nesrine Benslimane, Frédéric Favreau, Marion Rassat, Laurence Richard, Sylvie Bourthoumieu, Cécile Laroche, Laurent Magy, Corinne Magdelaine, Franck Sturtz, Anne-Sophie Lia and Pierre-Antoine Faye
Biomedicines 2021, 9(8), 945; https://doi.org/10.3390/biomedicines9080945 - 2 Aug 2021
Cited by 15 | Viewed by 4024
Abstract
Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) gene have been associated with demyelinating and axonal forms of Charcot-Marie-Tooth (CMT) disease, the most frequent hereditary peripheral neuropathy in humans. Previous studies reported the prevalent GDAP1 expression in neural tissues and [...] Read more.
Mutations in the ganglioside-induced differentiation associated protein 1 (GDAP1) gene have been associated with demyelinating and axonal forms of Charcot-Marie-Tooth (CMT) disease, the most frequent hereditary peripheral neuropathy in humans. Previous studies reported the prevalent GDAP1 expression in neural tissues and cells, from animal models. Here, we described the first GDAP1 functional study on human induced-pluripotent stem cells (hiPSCs)-derived motor neurons, obtained from normal subjects and from a CMT2H patient, carrying the GDAP1 homozygous c.581C>G (p.Ser194*) mutation. At mRNA level, we observed that, in normal subjects, GDAP1 is mainly expressed in motor neurons, while it is drastically reduced in the patient’s cells containing a premature termination codon (PTC), probably degraded by the nonsense-mediated mRNA decay (NMD) system. Morphological and functional investigations revealed in the CMT patient’s motor neurons a decrease of cell viability associated to lipid dysfunction and oxidative stress development. Mitochondrion is a key organelle in oxidative stress generation, but it is also mainly involved in energetic metabolism. Thus, in the CMT patient’s motor neurons, mitochondrial cristae defects were observed, even if no deficit in ATP production emerged. This cellular model of hiPSCs-derived motor neurons underlines the role of mitochondrion and oxidative stress in CMT disease and paves the way for new treatment evaluation. Full article
Show Figures

Figure 1

18 pages, 4161 KiB  
Article
Mutations in GDAP1 Influence Structure and Function of the Trans-Golgi Network
by Katarzyna Binięda, Weronika Rzepnikowska, Damian Kolakowski, Joanna Kaminska, Andrzej Antoni Szczepankiewicz, Hanna Nieznańska, Andrzej Kochański and Dagmara Kabzińska
Int. J. Mol. Sci. 2021, 22(2), 914; https://doi.org/10.3390/ijms22020914 - 18 Jan 2021
Cited by 13 | Viewed by 3504
Abstract
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 [...] Read more.
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. Full article
Show Figures

Figure 1

14 pages, 3243 KiB  
Article
Pathogenic Effect of GDAP1 Gene Mutations in a Yeast Model
by Weronika Rzepnikowska, Joanna Kaminska, Dagmara Kabzińska and Andrzej Kochański
Genes 2020, 11(3), 310; https://doi.org/10.3390/genes11030310 - 14 Mar 2020
Cited by 12 | Viewed by 3593
Abstract
The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect [...] Read more.
The question of whether a newly identified sequence variant is truly a causative mutation is a central problem of modern clinical genetics. In the current era of massive sequencing, there is an urgent need to develop new tools for assessing the pathogenic effect of new sequence variants. In Charcot-Marie-Tooth disorders (CMT) with their extreme genetic heterogeneity and relatively homogenous clinical presentation, addressing the pathogenic effect of rare sequence variants within 80 CMT genes is extremely challenging. The presence of multiple rare sequence variants within a single CMT-affected patient makes selection for the strongest one, the truly causative mutation, a challenging issue. In the present study we propose a new yeast-based model to evaluate the pathogenic effect of rare sequence variants found within the one of the CMT-associated genes, GDAP1. In our approach, the wild-type and pathogenic variants of human GDAP1 gene were expressed in yeast. Then, a growth rate and mitochondrial morphology and function of GDAP1-expressing strains were studied. Also, the mutant GDAP1 proteins localization and functionality were assessed in yeast. We have shown, that GDAP1 was not only stably expressed but also functional in yeast cell, as it influenced morphology and function of mitochondria and altered the growth of a mutant yeast strain. What is more, the various GDAP1 pathogenic sequence variants caused the specific for them effect in the tests we performed. Thus, the proposed model is suitable for validating the pathogenic effect of known GDAP1 mutations and may be used for testing of unknown sequence variants found in CMT patients. Full article
(This article belongs to the Special Issue Genetic Aspects of Yeast: Cell Biology, Ecology and Biotechnology)
Show Figures

Figure 1

17 pages, 775 KiB  
Review
Calcium Deregulation and Mitochondrial Bioenergetics in GDAP1-Related CMT Disease
by Paloma González-Sánchez, Jorgina Satrústegui, Francesc Palau and Araceli del Arco
Int. J. Mol. Sci. 2019, 20(2), 403; https://doi.org/10.3390/ijms20020403 - 18 Jan 2019
Cited by 21 | Viewed by 7372
Abstract
The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but [...] Read more.
The pathology of Charcot-Marie-Tooth (CMT), a disease arising from mutations in different genes, has been associated with an impairment of mitochondrial dynamics and axonal biology of mitochondria. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause several forms of CMT neuropathy, but the pathogenic mechanisms involved remain unclear. GDAP1 is an outer mitochondrial membrane protein highly expressed in neurons. It has been proposed to play a role in different aspects of mitochondrial physiology, including mitochondrial dynamics, oxidative stress processes, and mitochondrial transport along the axons. Disruption of the mitochondrial network in a neuroblastoma model of GDAP1-related CMT has been shown to decrease Ca2+ entry through the store-operated calcium entry (SOCE), which caused a failure in stimulation of mitochondrial respiration. In this review, we summarize the different functions proposed for GDAP1 and focus on the consequences for Ca2+ homeostasis and mitochondrial energy production linked to CMT disease caused by different GDAP1 mutations. Full article
(This article belongs to the Special Issue Research on Charcot-Marie-Tooth Disease, from Molecules to Therapy)
Show Figures

Figure 1

13 pages, 1233 KiB  
Case Report
Rapid Identification of Pathogenic Variants in Two Cases of Charcot-Marie-Tooth Disease by Gene-Panel Sequencing
by Chi-Chun Ho, Shuk-Mui Tai, Edmond Chi-Nam Lee, Timothy Shin-Heng Mak, Timothy Kam-Tim Liu, Victor Wai-Lun Tang and Wing-Tat Poon
Int. J. Mol. Sci. 2017, 18(4), 770; https://doi.org/10.3390/ijms18040770 - 5 Apr 2017
Cited by 12 | Viewed by 4678
Abstract
Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by [...] Read more.
Charcot-Marie-Tooth disease (CMT) is a common inherited peripheral neuropathy affecting up to 1 in 1214 of the general population with more than 60 nuclear genes implicated in its pathogenesis. Traditional molecular diagnostic pathways based on relative prevalence and clinical phenotyping are limited by long turnaround time, population-specific prevalence of causative variants and inability to assess multiple co-existing variants. In this study, a CMT gene panel comprising 27 genes was used to uncover the pathogenic mutations in two index patients. The first patient is a 15-year-old boy, born of consanguineous parents, who has had frequent trips and falls since infancy, and was later found to have inverted champagne bottle appearance of bilateral legs and foot drop. His elder sister is similarly affected. The second patient is a 37-year-old woman referred for pre-pregnancy genetic diagnosis. During early adulthood, she developed progressive lower limb weakness, difficulties in tip-toe walking and thinning of calf muscles. Both patients are clinically compatible with CMT, have undergone multiple genetic testings and have not previously received a definitive genetic diagnosis. Patients 1 and 2 were found to have pathogenic homozygous HSPB1:NM_001540:c.250G>A (p.G84R) variant and heterozygous GDAP1:NM_018972:c.358C>T (p.R120W) variant, respectively. Advantages and limitations of the current approach are discussed. Full article
(This article belongs to the Section Molecular Pathology, Diagnostics, and Therapeutics)
Show Figures

Figure 1

Back to TopTop