{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T17:17:39Z","timestamp":1787764659924,"version":"build-2784847793"},"reference-count":32,"publisher":"The Company of Biologists","issue":"4","license":[{"start":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T00:00:00Z","timestamp":1680480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Barcelona: Universitat de Barcelona"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,4,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>GDAP1 pathogenic variants cause Charcot-Marie-Tooth (CMT) disease, the most common hereditary motor and sensory neuropathy. CMT-GDAP1 can be axonal or demyelinating, with autosomal dominant or recessive inheritance, leading to phenotypic heterogeneity. Recessive GDAP1 variants cause a severe phenotype, whereas dominant variants are associated with a milder disease course. GDAP1 is an outer mitochondrial membrane protein involved in mitochondrial membrane contact sites (MCSs) with the plasmatic membrane, the endoplasmic reticulum (ER), and lysosomes. In GDAP1-deficient models, the pathophysiology includes morphological defects in mitochondrial network and ER, impaired Ca2+ homeostasis, oxidative stress, and mitochondrial MCSs defects. Nevertheless, the underlying pathophysiology of dominant variants is less understood.<\/jats:p>\n               <jats:p>Here, we study the effect upon mitochondria\u2013lysosome MCSs of two GDAP1 clinical variants located in the \u03b1-loop interaction domain of the protein. p.Thr157Pro dominant variant causes the increase in these MCSs that correlates with a hyper-fissioned mitochondrial network. In contrast, p.Arg161His recessive variant, which is predicted to significantly change the contact surface of GDAP1, causes decreased contacts with more elongated mitochondria.<\/jats:p>\n               <jats:p>Given that mitochondria\u2013lysosome MCSs regulate Ca2+ transfer from the lysosome to mitochondria, our results support that GDAP1 clinical variants have different consequences for Ca2+ handling and that could be primary insults determining differences in severity between dominant and recessive forms of the disease.<\/jats:p>","DOI":"10.1242\/bio.059707","type":"journal-article","created":{"date-parts":[[2023,3,13]],"date-time":"2023-03-13T10:24:40Z","timestamp":1678703080000},"source":"Crossref","is-referenced-by-count":14,"title":["Differential effects of Mendelian <i>GDAP1<\/i> clinical variants on mitochondria-lysosome membrane contacts sites"],"prefix":"10.1242","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5196-5262","authenticated-orcid":false,"given":"Lara","family":"Cantarero","sequence":"first","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine \u2013 IPER, Institut de Recerca Sant Joan de D\u00e9u, 08950 1 , Barcelona , Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, 08950 2 , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3995-7590","authenticated-orcid":false,"given":"Gisela","family":"Garc\u00eda-Vargas","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine \u2013 IPER, Institut de Recerca Sant Joan de D\u00e9u, 08950 1 , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6790-6988","authenticated-orcid":false,"given":"Janet","family":"Hoenicka","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine \u2013 IPER, Institut de Recerca Sant Joan de D\u00e9u, 08950 1 , Barcelona , Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, 08950 2 , Barcelona , Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8635-5421","authenticated-orcid":false,"given":"Francesc","family":"Palau","sequence":"additional","affiliation":[{"name":"Laboratory of Neurogenetics and Molecular Medicine \u2013 IPER, Institut de Recerca Sant Joan de D\u00e9u, 08950 1 , Barcelona , Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), ISCIII, 08950 2 , Barcelona , Spain"},{"name":"Hospital Sant Joan de D\u00e9u, 08950 3 Department of Genetic Medicine \u2013 IPER , , Barcelona , Spain"},{"name":"University of Barcelona, 08036 4 Division of Pediatrics, Faculty of Medicine and Health Sciences , , Barcelona , Spain"},{"name":"ERN-ITHACA 5"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2023,4,3]]},"reference":[{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"720","DOI":"10.1016\/S0960-8966(03)00093-2","article-title":"Identification of novel GDAP1 mutations causing autosomal recessive Charcot-Marie-Tooth disease","volume":"13","author":"Ammar","year":"2003","journal-title":"Neuromuscul. Disord."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"e1005115","DOI":"10.1371\/journal.pgen.1005115","article-title":"Lack of GDAP1 induces neuronal calcium and mitochondrial defects in a knockout mouse model of charcot-marie-tooth neuropathy","volume":"11","author":"Barneo-Munoz","year":"2015","journal-title":"PLoS Genet."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/ng796","article-title":"Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A\/8q21","volume":"30","author":"Baxter","year":"2002","journal-title":"Nat. Genet."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"3589","DOI":"10.1093\/hmg\/ddaa243","article-title":"Mitochondria-lysosome membrane contacts are defective in GDAP1-related Charcot-Marie-Tooth disease","volume":"29","author":"Cantarero","year":"2021","journal-title":"Hum. Mol. Genet."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"31","DOI":"10.1016\/j.expneurol.2010.09.006","article-title":"Mitochondrial dysfunction and pathophysiology of Charcot-Marie-Tooth disease involving GDAP1 mutations","volume":"227","author":"Cassereau","year":"2011","journal-title":"Exp. Neurol."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"105300","DOI":"10.1016\/j.nbd.2021.105300","article-title":"Mitochondria and calcium defects correlate with axonal dysfunction in GDAP1-related Charcot-Marie-Tooth mouse model","volume":"152","author":"Civera-Tregon","year":"2021","journal-title":"Neurobiol. Dis."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1136\/jmg.2004.022178","article-title":"Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect","volume":"42","author":"Claramunt","year":"2005","journal-title":"J. Med. Genet."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1038\/ng798","article-title":"The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease","volume":"30","author":"Cuesta","year":"2002","journal-title":"Nat. Genet."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"13843","DOI":"10.1074\/jbc.M808515200","article-title":"Loss of PINK1 function promotes mitophagy through effects on oxidative stress and mitochondrial fission","volume":"284","author":"Dagda","year":"2009","journal-title":"J. Biol. Chem."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"42993","DOI":"10.1038\/srep42993","article-title":"CMT-linked loss-of-function mutations in GDAP1 impair store-operated Ca(2+) entry-stimulated respiration","volume":"7","author":"Gonzalez-Sanchez","year":"2017","journal-title":"Sci. Rep."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"7192","DOI":"10.1096\/fj.202000110R","article-title":"Structural and functional divergence of GDAP1 from the glutathione S-transferase superfamily","volume":"34","author":"Googins","year":"2020","journal-title":"FASEB J."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"36930","DOI":"10.1038\/srep36930","article-title":"Glutathione-conjugating and membrane-remodeling activity of GDAP1 relies on amphipathic C-terminal domain","volume":"6","author":"Huber","year":"2016","journal-title":"Sci. Rep."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1016\/j.bbabio.2008.12.005","article-title":"Calcium regulation of mitochondria motility and morphology","volume":"1787","author":"Jeyaraju","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"176","DOI":"10.1093\/molbev\/msh013","article-title":"Evolutionary and structural analyses of GDAP1, involved in Charcot-Marie-Tooth disease, characterize a novel class of glutathione transferase-related genes","volume":"21","author":"Marco","year":"2004","journal-title":"Mol. Biol. Evol."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"631232","DOI":"10.3389\/fmolb.2020.631232","article-title":"Structure of the complete dimeric human GDAP1 core domain provides insights into ligand binding and clustering of disease mutations","volume":"7","author":"Nguyen","year":"2021","journal-title":"Front. Mol. Biosci."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1083\/jcb.200507087","article-title":"Ganglioside-induced differentiation associated protein 1 is a regulator of the mitochondrial network: new implications for Charcot-Marie-Tooth disease","volume":"170","author":"Niemann","year":"2005","journal-title":"J. Cell Biol."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1016\/j.nbd.2009.09.011","article-title":"GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance","volume":"36","author":"Niemann","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"1087","DOI":"10.1093\/hmg\/ddi121","article-title":"GDAP1, the protein causing Charcot-Marie-Tooth disease type 4A, is expressed in neurons and is associated with mitochondria","volume":"14","author":"Pedrola","year":"2005","journal-title":"Hum. Mol. Genet."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1111\/j.1582-4934.2007.00158.x","article-title":"Cell expression of GDAP1 in the nervous system and pathogenesis of Charcot-Marie-Tooth type 4A disease","volume":"12","author":"Pedrola","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"19266","DOI":"10.1073\/pnas.2003236117","article-title":"Mitochondria-lysosome contacts regulate mitochondrial Ca(2+) dynamics via lysosomal TRPML1","volume":"117","author":"Peng","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"784880","DOI":"10.3389\/fnins.2022.784880","article-title":"Mitochondrial dynamics and mitochondria-lysosome contacts in neurogenetic diseases","volume":"16","author":"Pijuan","year":"2022","journal-title":"Front. Neurosci."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.nbd.2013.03.010","article-title":"Silencing of the Charcot-Marie-Tooth disease-associated gene GDAP1 induces abnormal mitochondrial distribution and affects Ca2+ homeostasis by reducing store-operated Ca2+ entry","volume":"55","author":"Pla-Martin","year":"2013","journal-title":"Neurobiol. Dis."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"2023040310104545000_","author":"Schrodinger","year":"2015"},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1038\/nmeth.2890","article-title":"MutationTaster2: mutation prediction for the deep-sequencing age","volume":"11","author":"Schwarz","year":"2014","journal-title":"Nat. Methods"},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1093\/brain\/awn228","article-title":"Vocal cord paresis and diaphragmatic dysfunction are severe and frequent symptoms of GDAP1-associated neuropathy","volume":"131","author":"Sevilla","year":"2008","journal-title":"Brain"},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1111\/j.1529-8027.2010.00286.x","article-title":"Phenotypical features of the p.R120W mutation in the GDAP1 gene causing autosomal dominant Charcot-Marie-Tooth disease","volume":"15","author":"Sivera","year":"2010","journal-title":"J. Peripher. Nerv. Syst."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"6677","DOI":"10.1038\/s41598-017-06894-6","article-title":"Distribution and genotype-phenotype correlation of GDAP1 mutations in Spain","volume":"7","author":"Sivera","year":"2017","journal-title":"Sci. Rep."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"1030","DOI":"10.1002\/humu.23892","article-title":"MetaDome: Pathogenicity analysis of genetic variants through aggregation of homologous human protein domains","volume":"40","author":"Wiel","year":"2019","journal-title":"Hum. Mutat."},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1038\/nature25486","article-title":"Mitochondria-lysosome contacts regulate mitochondrial fission via RAB7 GTP hydrolysis","volume":"554","author":"Wong","year":"2018","journal-title":"Nature"},{"key":"2023040310104545000_","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1212\/WNL.0b013e318228fc70","article-title":"Dominant GDAP1 mutations cause predominantly mild CMT phenotypes","volume":"77","author":"Zimon","year":"2011","journal-title":"Neurology"}],"container-title":["Biology Open"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.logists.com\/bio\/bio\/article-pdf\/doi\/10.1242\/bio.059707\/2644443\/bio059707.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.logists.com\/bio\/bio\/article-pdf\/doi\/10.1242\/bio.059707\/2780635\/bio059707.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.logists.com\/bio\/bio\/article-pdf\/doi\/10.1242\/bio.059707\/2780635\/bio059707.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,4,3]],"date-time":"2023-04-03T10:23:30Z","timestamp":1680517410000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/bio\/article\/12\/4\/bio059707\/306219\/Differential-effects-of-Mendelian-GDAP1-clinical"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,4,3]]},"references-count":32,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2023,4,15]]}},"URL":"https:\/\/doi.org\/10.1242\/bio.059707","relation":{},"ISSN":["2046-6390"],"issn-type":[{"value":"2046-6390","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,4,3]]},"article-number":"bio059707"}}