TABLE 1.
Genes mutated in axonal and intermediate CMT.
| Gene/CMT subtype/OMIM Code | Function | References |
| AARS1/CMT2N/613287 | Catalyzes the attachment of alanine to tRNA. | McLaughlin et al., 2012; Zhao Z. et al., 2012; Bansagi et al., 2015; Dohrn et al., 2017; Weterman et al., 2018 |
| ATP1A1/CMT2DD/618036 | Catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane. | Lassuthova et al., 2018 |
| BAG3/CMT2* | Acts as a nucleotide-exchange factor promoting the release of ADP from the HSP70 and HSC70 proteins thereby triggering client/substrate protein release. Has anti-apoptotic activity. Plays a role in cytoskeletal proteostasis and dynamics. | Kim et al., 2018; Shy et al., 2018 |
| BSCL2/CMT2/619112* | Plays a crucial role in the formation of lipid droplets. Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplet contacts. Binds anionic phospholipids including phosphatidic acid. | Chaudhry et al., 2013 |
| DCTN2/CMT2* | Component of a large macromolecular complex required for the cytoplasmic dynein-driven movement of organelles along microtubules. Pays a role in prometaphase chromosome alignment and spindle organization during mitosis. | Braathen et al., 2016 |
| DGAT2/CMT2 | Required for synthesis and storage of intracellular triglycerides. | Hong et al., 2016 |
| DHTKD1/CMT2Q/615025 | Catalyzes the overall conversion of 2-oxoglutarate to succinyl-CoA and CO2. | Baets et al., 2014; Dohrn et al., 2017; Zhao et al., 2019 |
| DNAJB2/CMT2T/604139 | Functions as a co-chaperone, activating the ATPase activity of chaperones of the HSP70/heat shock protein 70 family. Contributes to the ubiquitin-dependent proteasomal degradation of misfolded proteins. | Gess et al., 2014; Lupo et al., 2016 |
| DNM2/CMT2M/602378; CMTDIB/606482* | Plays an important role in vesicular trafficking processes, in particular endocytosis. Involved in producing microtubule bundles. Involved in cytokinesis. | Echaniz-Laguna et al., 2007; Bitoun et al., 2008; Haberlová et al., 2011; González-Jamett et al., 2014; Saghira et al., 2018 |
| DYNC1H1/CMT2O/614228* | Acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules. Plays a role in mitotic spindle assembly and metaphase plate congression. | Weedon et al., 2011 |
| GARS1/CMT2D/601472 | Catalyzes the attachment of glycine to tRNA | James et al., 2006; Xie et al., 2006; Hamaguchi et al., 2010; Motley et al., 2011; Morelli et al., 2017 |
| GDAP1/CMT2K/607831; CMTRIA608340/; CMT4A/214400* | Regulates the mitochondrial network by promoting mitochondrial fission. Proposed roles in mitochondrial transport, redox processes, calcium homeostasis, and energy production. | Baxter et al., 2002; Cuesta et al., 2002; Ammar et al., 2003; Senderek et al., 2003; Di Maria et al., 2004; Zhang et al., 2004; Baránková et al., 2007; Kabzińska et al., 2007; Auer-Grumbach et al., 2008; Rougeot et al., 2008; Xin et al., 2008; Moroni et al., 2009; Sahin-Calapoglu et al., 2009a,b; Cassereau et al., 2011; Fusco et al., 2011; Zimoń et al., 2011, 2015; Vital et al., 2012; Auranen et al., 2013; Manganelli et al., 2015; Martin et al., 2015; Dohrn et al., 2017; Ho et al., 2017; Martí et al., 2017; Yoshimura et al., 2017; He et al., 2018; Masingue et al., 2018; Rzepnikowska and Kochański, 2018; Mai et al., 2019; Qin et al., 2019 |
| HARS1/CMT2W/616625 | Catalyzes the attachment of histidine to tRNA. | Baets et al., 2014 |
| HINT1/CMT2/137200 | Hydrolyzes purine nucleotide phosphoramidates with a single phosphate group. | Baets et al., 2014; Laššuthová et al., 2015; Zimoń et al., 2015; Dohrn et al., 2017 |
| HSPB1/CMT2F/606595* | Functions as a molecular chaperone maintaining denatured proteins in a folding-competent state. Plays a role in stress resistance and actin organization. Regulates numerous biological processes including phosphorylation and axonal transport of neurofilament proteins. | Liu et al., 2005; Tang et al., 2005; Chung et al., 2008; Houlden et al., 2008; Solla et al., 2010; Amornvit et al., 2017; Dohrn et al., 2017; Ho et al., 2017; Weeks et al., 2018 |
| HSPB8/CMT2L/608673* | Displays temperature-dependent chaperone activity. Forms complex with BAG3. | Nicholson et al., 2009 |
| IGHMBP2/CMT2S/616155 | 5′ to 3′ helicase that unwinds RNA and DNA duplices. Acts as a transcription regulator. | Cottenie et al., 2014; Wagner et al., 2015; Dohrn et al., 2017; Yuan et al., 2017 |
| JPH1/CMT2K/607831 | Contributes to the formation of junctional membrane complexes which link the plasma membrane with the endoplasmic or sarcoplasmic reticulum in excitable cells. Provides a structural foundation for functional cross-talk between the cell surface and intracellular calcium release channels. | Pla-Martín et al., 2015; Kanwal and Perveen, 2019 |
| KIF1B/CMT2A1/118210* | Motor for anterograde transport of mitochondria. | Nakagawa and Takashima, 2003; Bissar-Tadmouri et al., 2004 |
| KIF5A/CMT2* | Microtubule-dependent motor required for slow axonal transport of neurofilament proteins. Contributes to the vesicular transport of VAPA, VAPB, SURF4, RAB11A, RAB11B and RTN3 proteins in neurons. | Dohrn et al., 2017 |
| LMNA/CMT2B1/605588 | Plays an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics. | De Sandre-Giovannoli et al., 2002; Chaouch et al., 2003; Hamadouche et al., 2008; Zhang et al., 2010; Liang et al., 2016; Dohrn et al., 2017 |
| LRSAM1/CMT2G/614436 | E3 ubiquitin-protein ligase. Bacterial recognition protein that defends the cytoplasm from invasive pathogens. Potential role in mitophagy? | Guernsey et al., 2010; Nicolaou et al., 2013; Dohrn et al., 2017 |
| MARS1/CMT2U/616280 | Catalyzes the attachment of methionine to tRNA. | Baets et al., 2014; Sun et al., 2017 |
| MED25/CMT2B2/605589 | A coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes. | Leal et al., 2009, 2018; Tazir et al., 2013 |
| MFN2/CMT2A2/609260* | Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion. Involved in the clearance of damaged mitochondria via mitophagy. Potential roles in mitochondria-ER contacts and mitochondrial transport. | Kijima et al., 2005; Lawson et al., 2005; Engelfried et al., 2006; Verhoeven et al., 2006; Zuchner et al., 2006; Loiseau et al., 2007; Muglia et al., 2007; Neusch et al., 2007; Del Bo et al., 2008; Calvo et al., 2009; Cartoni and Martinou, 2009; Braathen et al., 2010; Ouvrier and Grew, 2010; Feely et al., 2011; McCorquodale et al., 2011; Park et al., 2012; Vital et al., 2012; Brožková et al., 2013; Chapman et al., 2013; Kotruchow et al., 2013; Lv et al., 2013, 2015; Vielhaber et al., 2013; Bergamin et al., 2014; Choi B. O. et al., 2015; Wang et al., 2015; Bannerman et al., 2016; Di Meglio et al., 2016; Neupauerová et al., 2016; Rudnik-Schöneborn et al., 2016; Tan et al., 2016; Werheid et al., 2016; Xie et al., 2016; Ando et al., 2017; Beręsewicz et al., 2017; Dohrn et al., 2017; El Fissi et al., 2018; Finsterer et al., 2018; Iapadre et al., 2018; Milley et al., 2018; Larrea et al., 2019; Xu et al., 2019 |
| MME/CMT2T/617017 | Biologically important in the destruction of opioid peptides. Able to cleave angiotensin. Involved in the degradation of atrial natriuretic factor. | Auer-Grumbach et al., 2016; Fujisawa et al., 2017 |
| MORC2/CMT2Z/616688 | Essential for epigenetic silencing by the HUSH complex. | Albulym et al., 2016 |
| MPV17/CMT2EE/618400* | Non-selective channel that modulates membrane potential under normal conditions and oxidative stress, and is involved in mitochondrial homeostasis. Involved in mitochondrial deoxynucleoside triphosphates pool homeostasis and mitochondrial DNA maintenance. | Choi Y. R. et al., 2015 |
| MPZ/CMT2J/607736; CMTDID/607791; CMT1B/118200 | Mediates adhesion between adjacent myelin wraps and ultimately drives myelin compaction. | Hayasaka et al., 1993; Pham-Dinh et al., 1993; Nelis et al., 1994; Latour et al., 1995; Blanquet-Grossard et al., 1996; Roa et al., 1996; Silander et al., 1996; Bissar-Tadmouri et al., 1999; De Jonghe et al., 1999; Lagueny et al., 1999; Quattrini et al., 1999; Senderek et al., 2000; Kochański et al., 2004; Kurihara et al., 2004; Bienfait et al., 2006; Sabet et al., 2006; Laurà et al., 2007; Lee et al., 2008; Mazzeo et al., 2008; Gallardo et al., 2009; Avila et al., 2010; Brozková et al., 2010; Kleffner et al., 2010; Choi et al., 2011; Høyer et al., 2011, 2014; Chavada et al., 2012; Maeda et al., 2012; Marttila et al., 2012; Rosberg et al., 2013; Speevak and Farrell, 2013; Bergamin et al., 2014; Leal et al., 2014; Sanmaneechai et al., 2015; Tokuda et al., 2015; Wang et al., 2015; Rudnik-Schöneborn et al., 2016; Werheid et al., 2016; Dohrn et al., 2017; He et al., 2018; Milley et al., 2018; Xu et al., 2019 |
| MT-ATP6/CMT2* | Mitochondrial membrane ATP synthase. Key component of the proton channel. | Pitceathly et al., 2012 |
| MYH14/CMT2/614369* | Conventional non-muscle myosin. Actin-dependent motor protein. Mediates mitochondrial fission. | Almutawa et al., 2019 |
| NAGLU/CMT2V/616491 | Involved in the degradation of heparan sulfate. | Tétreault et al., 2015 |
| NEFH/CMT2CC/616924* | Component of neurofilaments, the most abundant cytoskeletal component of myelinated axons. | Bian et al., 2018 |
| NEFL/CMT2E/607684* | Component of neurofilaments, the most abundant cytoskeletal component of myelinated axons. Regulates mitochondrial morphology. | Lupski, 2000; Luo et al., 2003; Fabrizi et al., 2007; Miltenberger-Miltenyi et al., 2007; Shin et al., 2008; Bhagavati et al., 2009; Berciano et al., 2016; Werheid et al., 2016; Dohrn et al., 2017; Horga et al., 2017; Fu and Yuan, 2018; Xu et al., 2019 |
| PNKP/CMT2B2/605589 | Plays a key role in the repair of DNA damage, functioning as part of both the non-homologous end-joining and base excision repair pathways. | Leal et al., 2018 |
| RAB7A/CMT2B/600882* | Key regulator in endo-lysosomal trafficking. Plays roles in growth-factor-mediated cell signaling, nutrient-transporter mediated nutrient uptake, neurotrophin transport in the axons of neurons and lipid metabolism. Regulates mitochondrial fission, mitophagy, and mitochondria-lysosome tethering. | Meggouh et al., 2006; Zhang et al., 2010; Manganelli et al., 2015 |
| SPG11/CMT2X/616668* | Plays a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport. | Montecchiani et al., 2016 |
| TRIM2/CMT2R/615490* | E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and of phosphorylated BCL2L11. | Baets et al., 2014; Pehlivan et al., 2015 |
| TRPV4/CMT2C/606071* | Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity. Some data supporting a role in regulating mitochondrial motility. | Klein et al., 2003; Deng et al., 2010; Manganelli et al., 2015; Dohrn et al., 2017 |
| VCP/CMT2Y/616687* | Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis. Involved in the formation of the transitional endoplasmic reticulum. Plays a role in the regulation of stress granule clearance. Involved in DNA damage response. Essential for the maturation of ubiquitin-containing autophagosomes and the clearance of ubiquitinated protein by autophagy and mitophagy. | Gonzalez et al., 2014 |
| C1ORF194/CMTDI | May affect intracellular Ca2+ homeostasis. | Sun et al., 2019 |
| GNB4/CMTDIF/615185 | Modulator/transducer in various transmembrane signaling systems. | Soong et al., 2013; Baets et al., 2014; Miura et al., 2017 |
| INF2/CMTDIE/614455* | Mediates actin polymerization at ER-mitochondria contact sites. Regulates mitochondrial morphology and motility. | Boyer et al., 2011a,b; Mademan et al., 2013; Rodriguez et al., 2013; Vallat et al., 2013; Caridi et al., 2014; Park et al., 2014; Jin et al., 2015; Werheid et al., 2016; Dohrn et al., 2017; Echaniz-Laguna and Latour, 2019; Fu et al., 2019 |
| SLC12A6/CMTDI/218000 | Mediates electroneutral potassium-chloride cotransport. | Lupo et al., 2016 |
| YARS1/CMTDIC/608323 | Catalyzes the attachment of tyrosine to its corresponding tRNA | Jordanova et al., 2006; Xie et al., 2007 |
| COX6A1/CMTRI/616039* | A subunit of the cytochrome c oxidase complex | Tamiya et al., 2014 |
| KARS1/CMTRIB/613641 | Catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria | McLaughlin et al., 2010 |
| PLEKHG5/CMTRIC/615376 | Activates the nuclear factor kappa B (NFKB1) signaling pathway. Also implicated in distal spinal muscular atrophy. | Kim et al., 2013 |
Genes that play a role in mitochondrial function and/or motility are marked with an asterisk.