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A role for the GDAP1 gene in the molecular pathogenesis of Charcot - Marie - Tooth disease

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In 2002 a series of mutations in the GDAP1 gene were reported in patients suffering from Charcot-Marie-Tooth disease manifesting as early–onset, progressive distal-muscle wasting and weakness. The molecular etiology of Charcot-Marie-Tooth -GDAP1 disease has been elucidated but its pathogenesis remains unclear, especially given the seemingly contradictory function of the GDAP1 protein. Expression of GDAP1 is observed almost exclusively in neuronal cells, however, the GDAP1 protein is present in mitochondria, where it plays a role in fission, a ubiquitous process occurring in all cells. While GDAP1 contains two glutathione S-transferase (GST) domains, its GST activity is in fact very limited. Additionally, despite GDAP1 affecting mitochondrial functionality, and hence being of great importance to cellular function, the GDAP1-associated Charcot–Marie–Tooth disease is mainly characterized by axonal degeneration. Finally, mutations in the GDAP1 gene may be inherited in a recessive or dominant manner. Given the way such varied observations are hard to reconcile with one another, the investigation of GDAP1 is at one and the same time a difficult but also challenging endeavour. The purpose of this review is to summarize the current knowledge on the GDAP1 protein and its function in the cell. A further part is the characterization of GDAP1-associated Charcot–Marie–Tooth disease, its symptoms and course, as well as an outlining of the possible mechanisms underpinning the disorder.

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Opis fizyczny



  • Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland
  • Neuromuscular Unit, Mossakowski Medical Research Centre Polish Academy of Sciences, Warsaw, Poland


  • Alexander C, Votruba M, Pesch UE, Thiselton DL, Mayer S, Moore A,Rodriguez M, Kellner U, Leo-Kottler B, Auburger G, Bhattacharya SS, Wissinger B (2000) OPA1, encoding a dynamin-related GTPase, is mutated in autosomal dominant optic atrophy linked to chromosome 3q28. Nat Genet 26: 211–215.
  • Auer-Grumbach M, Fischer C, Papić L, John E, Plecko B, Bittner RE, Bernert G, Pieber TR, Miltenberger G, Schwarz R, Windpassinger C, Grill F, Timmerman V, Speicher MR, Janecke AR (2008) Two novel mutations in the GDAP1 and PRX genes in early onset Charcot-Marie-Tooth syndrome. Neuropediatrics 39: 33–38.
  • Azzedine H, Ruberg M, Ente D, Gilardeau C, Périé S, Wechsler B, Brice A, LeGuern E, Dubourg O (2003) Variability of disease progression in a family with autosomal recessive CMT associated with a S194X and new R310Q mutation in the GDAP1 gene. Neuromuscul Disord 134: 341 346.
  • Barneo-Muñoz M, Juárez P, Civera-Tregón A, Yndriago L, Pla-Martin D, Zenker J, Cuevas-Martín C, Estela A, Sánchez-Aragó M, Forteza-Vila J, Cuezva JM, Chrast R, Palau F (2015) Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy. PLoS Genet 11: e1005115.
  • Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, Hentati F, Ben Hamida M, Bel S, Stenger JE, Gilbert JR, Pericak-Vance MA, Vance JM (2002) Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet 30: 21–22.
  • Ben Othmane K, Hentati F, Lennon F, Ben Hamida C, Blel S, Roses AD, Pericak-Vance MA, Ben Hamida M, Vance JM (1993) Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. Hum Mol Genet 2: 1625–1628.
  • Bertholet AM, Delerue T, Millet AM, Moulis MF, David C, Daloyau M, Arnauné-Pelloquin L, Davezac N, Mils V, Miquel MC, Rojo M, Belenguer P (2016) Mitochondrial fusion/fission dynamics in neurodegeneration and neuronal plasticity. Neurobiol Dis 90: 3–19.
  • Brown MD, Trounce IA, Jun AS, Allen JC, Wallace DC (2000) Functional analysis of lymphoblast and cybrid mitochondria containing the 3460, 11778, or 14484 Leber’s hereditary optic neuropathy mitochondrial DNA mutation. J Biol Chem 275: 39831–39836.
  • Cassereau J, Chevrollier A, Gueguen N, Desquiret V, Verny C, Nicolas G, Dubas F, Amati-Bonneau P, Reynier P, Bonneau D, Procaccio V (2011) Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations. Exp Neurol 227: 31–41.
  • Cassereau J, Chevrollier A, Gueguen N, Malinge MC, Letournel F, Nicolas G, Richard L, Ferre M, Verny C, Dubas F, Procaccio V, Amati-Bonneau P, Bonneau D, Reynier P (2009) Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). Neurogenetics 10: 145–150.
  • Chen H, Detmer SA, Ewald AJ, Griffin EE, Fraser SE, Chan DC (2003) Mitofusins Mfn1 and Mfn2 coordinately regulate mitochondrial fusion and are essential for embryonic development. J Cell Biol 160: 189–200.
  • Chen H, McCaffery JM, Chan DC (2007) Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell 130: 548–562.
  • Chen X, Guo C, Kong J (2012) Oxidative stress in neurodegenerative diseases. Neural Regen Res 7: 376–385.
  • Claramunt R, Pedrola L, Sevilla T, López de Munain A, Berciano J, Cuesta A, Sánchez-Navarro B, Millán JM, Saifi GM, Lupski JR, Vílchez JJ, Espinós C, Palau F (2005) Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect. J Med Genet 42: 358–365.
  • Cuesta A, Pedrola L, Sevilla T, García-Planells J, Chumillas MJ, Mayordomo F, LeGuern E, Marín I, Vílchez JJ, Palau F (2002) The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet 30: 22–25.
  • De Sandre-Giovannoli A, Chaouch M, Boccaccio I, Bernard R, Delague V, Grid D, Vallat JM, Lévy N, Mégarbané A (2003) Phenotypic and genetic exploration of severe demyelinating and secondary axonal neuropathies resulting from GDAP1 nonsense and splicing mutations. J Med Genet 40: e87.
  • Delettre C, Lenaers G, Griffoin JM, Gigarel N, Lorenzo C, Belenguer P, Pelloquin L, Grosgeorge J, Turc-Carel C, Perret E, Astarie-Dequeker C, Lasquellec L, Arnaud B, Ducommun B, Kaplan J, Hamel CP (2000) Nuclear gene OPA1, encoding a mitochondrial dynamin-related protein, is mutated in dominant optic atrophy. Nat Genet 26: 207–210.
  • Dyck PJ, Lambert EH (1968) Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. II. Neurologic, genetic, and electrophysiologic findings in various neuronal degenerations. Arch Neurol 18: 619–625.
  • Estela A, Pla-Martín D, Sánchez-Piris M, Sesaki H, Palau F (2011) Charcot-Marie-Tooth-related gene GDAP1 complements cell cycle delay at G2/M phase in Saccharomyces cerevisiae fis1 gene-defective cells. J BiolChem 286: 36777–36786.
  • Friedman JR, Lackner LL, West M, DiBenedetto JR, Nunnari J, Voeltz GK (2011) ER tubules mark sites of mitochondrial division. Science 334: 358–362.
  • Fu J, Dai S, Lu Y, Wu R, Wang Z, Yuan Y, Lv H (2017) Similar clinical, pathological, and genetic features in Chinese patients with autosomal recessive and dominant Charcot-Marie-Tooth disease type 2K. Neuromuscul Disord 27: 760-765.
  • Gao J, Wang L, Liu J, Xie F, Su B, Wang X (2017) Abnormalities of mitochondrial dynamics in neurodegenerative diseases. Antioxidants (Basel) 6: 25.
  • González-Sánchez P, Pla-Martín D, Martínez-Valero P, Rueda CB, Calpena E, Del Arco A, Palau F, Satrústegui J (2017) CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca(2+) entry-stimulated respiration. Sci Rep 7: 42993.
  • Haidar M, Timmerman V (2017) Autophagy as an emerging common pathomechanism in inherited peripheral neuropathies. Front Mol Neurosci 10: 143.
  • Hayashi G, Cortopassi G (2015) Oxidative stress in inherited mitochondrial diseases. Free Radic Biol Med 88: 10–17.
  • Herrera-Cruz MS, Simmen T (2017) Of yeast, mice and men: MAMs come in two flavors. Biol Direct 12: 3.
  • Huber N, Bieniossek C, Wagner KM, Elsässer HP, Suter U, Berger I, Niemann A (2016) Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain. Sci Rep 6: 36930.
  • Huber N, Guimaraes S, Schrader M, Suter U, Niemann A (2013) Charcot-Marie-Tooth disease-associated mutants of GDAP1 dissociate its roles in peroxisomal and mitochondrial fission. EMBO Rep 14: 545–552.
  • Kabzinska D, Drac H, Rowinska-Marcinska K, Fidzianska A, Kochanski A, Hausmanowa-Petrusewicz I (2006) Early onset Charcot-Marie-Tooth disease caused by a homozygous Leu239Phe mutation in the GDAP1 gene. Acta Myol 25: 34–37.
  • Kabzińska D, Kochański, A, Drac H, Ryniewicz B, Rowińska-Marcińska K, Hausmanowa-Petrusewicz I (2005) Autosomal recessive axonal form of Charcot-Marie-Tooth disease caused by compound heterozygous 3′-splice site and Ser130Cys mutation in the GDAP1 gene. Neuropediatrics 36: 206–209.
  • Kabzińska D, Niemann A, Drac H, Huber N, Potulska-Chromik A, Hausmanowa-Petrusewicz I, Suter U, Kochański A (2011) A new missense GDAP1 mutation disturbing targeting to the mitochondrial membrane causes a severe form of AR-CMT2C disease. Neurogenetics 12: 145–153.
  • Korsten A, de Coo IFM, Spruijt L, de Wit LEA, Smeets HJM, Sluiter W (2010) Patients with Leber hereditary optic neuropathy fail to compensate impaired oxidative phosphorylation. Biochim Biophys Acta 1797: 197–203.
  • Krols M, van Isterdael G, Asselbergh B, Kremer A, Lippens S, Timmerman V, Janssens S (2016) Mitochondria-associated membranes as hubs for neurodegeneration. Acta Neuropathol 131: 505–523.
  • Kudin AP, Bimpong-Buta NYB, Vielhaber S, Elger CE, Kunz WS (2004) Characterization of superoxide-producing sites in isolated brain mitochondria. J Biol Chem 279: 4127–4135.
  • Lackner LL (2014) Shaping the dynamic mitochondrial network. BMC Biol 12: 35.
  • Lee S, Sheck L, Crowston JG, Van Bergen NJ, O'Neill EC, O'Hare F, Kong YX, Chrysostomou V, Vincent AL, Trounce IA (2012) Impaired complex-I-linked respiration and ATP synthesis in primary open-angle glaucoma patient lymphoblasts. Invest Ophthalmol Vis Sci 53: 2431–2437.
  • Li Z, Okamoto KI, Hayashi Y, Sheng M (2004) The importance of dendritic mitochondria in the morphogenesis and plasticity of spines and synapses. Cell 119: 873–887.
  • Liu H, Nakagawa T, Kanematsu T, Uchida T, Tsuji S (1999) Isolation of 10 differentially expressed cDNAs in differentiated Neuro2a cells induced through controlled expression of the GD3 synthase gene. J Neurochem 72: 1781–1790.
  • López Del Amo V, Palomino-Schätzlein M, Seco-Cervera M, García-Giménez JL, Pallardó FV, Pineda-Lucena A, Galindo MI (2017) A Drosophila model of GDAP1 function reveals the involvement of insulin signalling in the mitochondria-dependent neuromuscular degeneration. Biochim Biophys Acta 1863: 801–809.
  • López Del Amo V, Seco-Cervera M, García-Giménez JL, Whitworth AJ, Pallardó FV, Galindo MI (2015) Mitochondrial defects and neuromuscular degeneration caused by altered expression of Drosophila Gdap1: implications for the Charcot-Marie-Tooth neuropathy. Hum Mol Genet 24: 21–36.
  • Manganelli F, Pisciotta C, Nolano M, Capponi S, Geroldi A, Topa A, Bellone E, Suls A, Mandich P, Santoro L (2012) A novel autosomal dominant GDAP1 mutation in an Italian CMT2 family. J Peripher Nerv Syst 17: 351–355.
  • Marco A, Cuesta A, Pedrola L, Palau F, Marín I (2004) Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes. Mol Biol Evol 21: 176–187.
  • Millecamps S, Julien JP (2013) Axonal transport deficits and neurodegenerative diseases. Nat Rev Neurosci 14: 161–176.
  • Misko A, Jiang S, Wegorzewska I, Milbrandt J, Baloh RH (2010) Mitofusin 2 is necessary for transport of axonal mitochondria and interacts with the Miro/Milton complex. J Neurosci 30: 4232–4240.
  • Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417: 1–13.
  • Nelis E, Erdem S, Van Den Bergh PY, Belpaire-Dethiou MC, Ceuterick C, Van Gerwen V, Cuesta A, Pedrola L, Palau F, Gabreëls-Festen AA, Verellen C, Tan E, Demirci M, Van Broeckhoven C, De Jonghe P, Topaloglu H, Timmerman V (2002) Mutations in GDAP1: autosomal recessive CMT with demyelination and axonopathy. Neurology 59: 1865–1872.
  • Niemann A, Huber N, Wagner KM, Somandin C, Horn M, Lebrun-Julien F, Angst B, Pereira JA, Halfter H, Welzl H, Feltri ML, Wrabetz L, Young P, Wessig C, Toyka KV, Suter U (2014) The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie-Tooth disease. Brain 137: 668–682.
  • Niemann A, Ruegg M, La Padula V, Schenone A, Suter U (2005) Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network. J Cell Biol 170: 1067–1078.
  • Niemann A, Wagner KM, Ruegg M, Suter U (2009) GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance. Neurobiol Dis 36: 509–520.
  • Noack R, Frede S, Albrecht P, Henke N, Pfeiffer A, Knoll K, Dehmel T, Meyer Zu Hörste G, Stettner M, Kieseier BC, Summer H, Golz S, Kochanski A, Wiedau-Pazos M, Arnold S, Lewerenz J, Methner A (2012) Charcot-Marie-Tooth disease CMT4A: GDAP1 increases cellular glutathione and the mitochondrial membrane potential. Hum Mol Genet 2: 150–162.
  • Parker WD, Parks JK, Swerdlow RH (2008) Complex I deficiency in Parkinson’s disease frontal cortex. Brain Res 1189: 215–218.
  • Pedrola L, Espert A, Valdés-Sánchez T, Sánchez-Piris M, Sirkowski EE, Scherer SS, Fariñas I, Palau F (2008) Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease. J Cell Mol Med 12: 679–689.
  • Pedrola L, Espert A, Wu X, Claramunt R, Shy ME, Palau F (2005) GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria. Hum Mol Genet 14: 1087–1094.
  • Pla-Martín D, Calpena E, Lupo V, Márquez C, Rivas E, Sivera R, Sevilla T, Palau F, Espinós C (2015) Junctophilin-1 is a modifier gene of GDAP1-related Charcot-Marie-Tooth disease. Hum Mol Genet 24: 213–229.
  • Pla-Martín D, Rueda CB, Estela A, Sánchez-Piris M, González-Sánchez P, Traba J, de la Fuente S, Scorrano L, Renau-Piqueras J, Alvarez J, Satrústegui J, Palau F (2013) Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+entry. Neurobiol Dis 55: 140–151.
  • Prieto J, León M, Ponsoda X, García-García F, Bort R, Serna E, Barneo-Muñoz M, Palau F, Dopazo J, López-García C, Torres J (2016) Dysfunctional mitochondrial fission impairs cell reprogramming. Cell Cycle 15: 3240–3250.
  • Ratajewski M, Pulaski L (2009) YY1-dependent transcriptional regulation of the human GDAP1 gene. Genomics 94: 407–413.
  • Safiulina D, Kaasik A (2013) Energetic and dynamic: how mitochondria meet neuronal energy demands. PLoS Biol 11: e1001755.
  • Santel A, Fuller MT (2001) Control of mitochondrial morphology by a human mitofusin. J Cell Sci 114: 867–874.
  • Schapira AH, Cooper JM, Dexter D, Clark JB, Jenner P, Marsden CD (1990) Mitochondrial complex I deficiency in Parkinson’s disease. J Neurochem 54: 823–827.
  • Schwarz TL (2013) Mitochondrial trafficking in neurons. Cold Spring Harb Perspect Biol 5: a011304–a011304.
  • Sebastián D, Hernández-Alvarez MI, Segalés J, Sorianello E, Muñoz JP, Sala D, Waget A, Liesa M, Paz JC, Gopalacharyulu P, Orešič M, Pich S, Burcelin R, Palacín M, Zorzano A (2012) Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis. Proc Natl Acad Sci U S A 109: 5523–5528.
  • Sevilla T, Jaijo T, Nauffal D, Collado D, Chumillas MJ, Vilchez JJ, Muelas N, Bataller L, Domenech R, Espinós C, Palau F (2008) Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy. Brain 131: 3051–3061.
  • Sheng ZH, Cai Q (2012) Mitochondrial transport in neurons: impact on synaptic homeostasis and neurodegeneration. Nat Rev Neurosci 13: 77–93.
  • Shield AJ, Murray TP, Board PG (2006) Functional characterisation of ganglioside-induced differentiation-associated protein 1 as a glutathione transferase. Biochem Biophys Res Commun 347: 859–866.
  • Sivera R, Frasquet M, Lupo V, García-Sobrino T, Blanco-Arias P, Pardo J, Fernández-Torrón R, de Munain AL, Márquez-Infante C, Villarreal L, Carbonell P, Rojas-García R, Segovia S, Illa I, Frongia AL, Nascimento A, Ortez C, García-Romero MDM, Pascual SI, Pelayo-Negro AL, Berciano J, Guerrero A, Casasnovas C, Camacho A, Esteban J, Chumillas MJ, Barreiro M, Díaz C, Palau F, Vílchez JJ, Espinós C, Sevilla T (2017) Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain. Sci Rep 7: 6677.
  • Vallat JM, Ouvrier RA, Pollard JD, Magdelaine C, Zhu D, Nicholson GA, Grew S, Ryan MM, Funalot B (2008) Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations. J Neuropathol Exp Neurol 67: 1097–1102.
  • Van Bergen NJ, Crowston JG, Craig JE, Burdon KP, Kearns LS, Sharma S, Hewitt AW, Mackey DA, Trounce IA (2015) Measurement of systemic mitochondrial function in advanced primary open-angle glaucoma and Leber hereditary optic neuropathy. PLoS One 10: e0140919.
  • Vance JE (2014) MAM (mitochondria-associated membranes) in mammalian cells: lipids and beyond. Biochim Biophys Acta 1841: 595–609.
  • Verstreken P, Ly CV, Venken KJT, Koh T-W, Zhou Y, Bellen HJ (2005) Synaptic mitochondria are critical for mobilization of reserve pool vesicles at Drosophila neuromuscular junctions. Neuron 47: 365–378.
  • Vos M, Lauwers E, Verstreken P (2010) Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease. Front Synaptic Neurosci 2: 139.
  • Wagner KM, Rüegg M, Niemann A, Suter U (2009) Targeting and function of the mitochondrial fission factor GDAP1 are dependent on its tail-anchor. PLoS One: e5160.
  • Wallace DC, Singh G, Lott MT, Hodge JA, Schurr TG, Lezza AM, Elsas LJ, Nikoskelainen EK (1988) Mitochondrial DNA mutation associated with Leber’s hereditary optic neuropathy. Science 242: 1427–1430.
  • Zimoń M, Baets J, Fabrizi GM, Jaakkola E, Kabzińska D, Pilch J, Schindler AB, Cornblath DR, Fischbeck KH, Auer-Grumbach M, Guelly C, Huber N, De Vriendt E, Timmerman V, Suter U, Hausmanowa-Petrusewicz I,Niemann A, Kochański A, De Jonghe P, Jordanova A (2011) Dominant GDAP1 mutations cause predominantly mild CMT phenotypes. Neurology 77: 540–548.
  • Züchner S, Mersiyanova IV, Muglia M, Bissar-Tadmouri N, Rochelle J, Dadali EL, Zappia M, Nelis E, Patitucci A, Senderek J, Parman Y,Evgrafov O, Jonghe PD, Takahashi Y, Tsuji S, Pericak-Vance MA, Quattrone A, Battaloglu E, Polyakov AV, Timmerman V, Schröder JM, Vance JM (2004) Mutations in the mitochondrial GTPase mitofusin 2 cause Charcot-Marie-Tooth neuropathy type 2A. Nat Genet 36: 449–451.

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