The Hexokinase 1 5′-UTR Mutation in Charcot–Marie–Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering
Abstract
:1. Introduction
2. Results
2.1. Mimicking CMT4G in HEK293T Cells Reveals a Defect in HK1/VDAC Interaction
2.2. Defect in HK1/VDAC Interaction Results in the Alteration of Mitochondrial Calcium Homeostasis
2.3. N-Terminus Peptide of Mutant HK1 Lacks the Ability to Block Mitochondrial Calcium Release through VDAC
2.4. Characterization of a Novel CMT4G Patient Series in the French Gispy Population
2.5. Mutated HK1 Is Unable to Interact with VDAC in PBMCs of CMT4G Patients
3. Discussion
4. Materials and Methods
4.1. Study Design and Patient Series
4.2. Plasmids and Reagents
4.3. Cell Culture and Transfection
4.4. PBMC Collection and Preparation
4.5. Immunoprecipitation
4.6. Immunocytochemistry
4.7. Videotracking Experiments
4.8. Data and Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Id. # Patient | Age at Onset of LL Weakness (Years) | Age at Onset of UL Weakness (Years) | Foot Deformities | CMTNS | MNCV Median (m/s) | CMAP Median, (mV) | SNAP |
---|---|---|---|---|---|---|---|
1 | 6 | 16 | +Arthrodesis | 24 | 16.7 (38) | 0.2 | NR |
2 | 6 | 15 | +Arthrodesis | 23 | NR (29) | NR | NR |
3 | 9 | 14 | + | 28 | NR (65) | NR | NR |
4 | 10 | 11 | + Arthrodesis | 12 | 11.2 (10) | 0.4 | NR |
5 | 7 | ND | - | ND | ND | ND | ND |
6 | 9 | ND | + | ND | ND | ND | ND |
7 | 7 | 16 | +Arthrodesis | ND | ND | ND | ND |
8 | 5 | 16 | - | 23 | 29 (9) | 1.5 | NR |
9 | 9 | 16 | - | 19 | 16.2 (21) | 1.4 | NR |
10 | 8 | ND | +Arthrodesis | 6 | 24.1 (10) | 5.6 | NR |
11 | 3 | ND | - | 1 | 28.9 (3) | 4.3 | NR |
12 | 4 | ND | + | 8 | 32 (9) | 1.93 | NR |
13 | 12 | 35 | - | 25 | ND | ND | ND |
14 | 10 | - | ND | - | - | - | - |
15 | 3 | - | ND | - | - | - | - |
16 | 3 | 16 | +Arthrodesis | 16 | 21 (36) | 0.59 | NR |
17 | 3 | - | ND | - | - | - | - |
18 | 10 | 10 | + Arthrodesis | 17 | 23.8 (12) | - | NR |
19 | 11 | 45 | ND | ND | ND | ND | ND |
20 | 13 | 20 | +Arthrodesis | - | - | - | - |
21 | 6 | ND | - | 6 | 30.6 (7) | 5.3 | NR |
22 | 10 | 14 | +Arthrodesis | ND | 22.2 (8) | 1.19 | NR |
23 | 5 | ND | - | ND | 24 (6) | 6.4 | NR |
24 | 4 | 7 | - | 20 | 16 (27) | 0.45 | NR |
25 | 12 | 8 | - | ND | ND | ND | ND |
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Ceprian, M.; Juntas-Morales, R.; Campbell, G.; Walther-Louvier, U.; Rivier, F.; Camu, W.; Esselin, F.; Echaniz-Laguna, A.; Stojkovic, T.; Bouhour, F.; et al. The Hexokinase 1 5′-UTR Mutation in Charcot–Marie–Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering. Int. J. Mol. Sci. 2024, 25, 4364. https://doi.org/10.3390/ijms25084364
Ceprian M, Juntas-Morales R, Campbell G, Walther-Louvier U, Rivier F, Camu W, Esselin F, Echaniz-Laguna A, Stojkovic T, Bouhour F, et al. The Hexokinase 1 5′-UTR Mutation in Charcot–Marie–Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering. International Journal of Molecular Sciences. 2024; 25(8):4364. https://doi.org/10.3390/ijms25084364
Chicago/Turabian StyleCeprian, Maria, Raul Juntas-Morales, Graham Campbell, Ulrike Walther-Louvier, François Rivier, William Camu, Florence Esselin, Andoni Echaniz-Laguna, Tanya Stojkovic, Françoise Bouhour, and et al. 2024. "The Hexokinase 1 5′-UTR Mutation in Charcot–Marie–Tooth 4G Disease Alters Hexokinase 1 Binding to Voltage-Dependent Anion Channel-1 and Leads to Dysfunctional Mitochondrial Calcium Buffering" International Journal of Molecular Sciences 25, no. 8: 4364. https://doi.org/10.3390/ijms25084364