{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T14:18:45Z","timestamp":1790691525898,"version":"4.1.0"},"reference-count":57,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T00:00:00Z","timestamp":1626825600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/M010996\/1"],"award-info":[{"award-number":["BB\/M010996\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/N015142\/1"],"award-info":[{"award-number":["BB\/N015142\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000268","name":"Biotechnology and Biological Sciences Research Council","doi-asserted-by":"publisher","award":["BB\/T00875X\/1"],"award-info":[{"award-number":["BB\/T00875X\/1"]}],"id":[{"id":"10.13039\/501100000268","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Glia"],"published-print":{"date-parts":[[2021,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Disruption of axon\u2010glia interactions in the peripheral nervous system has emerged as a major cause of arthrogryposis multiplex congenita (AMC), a condition characterized by multiple congenital postural abnormalities involving the major joints. Several genes crucially important to the biology of Schwann cells have now been implicated with AMC. One such gene is LGI4 which encodes a secreted glycoprotein. LGI4 is expressed and secreted by Schwann cells and binds its receptor ADAM22 on the axonal membrane to drive myelination. Homozygous mutations in LGI4 or ADAM22 results in severe congenital hypomyelination and joint contractures in mice. Recently bi\u2010allelic LGI4 loss of function mutations has been described in three unrelated families with severe AMC. Two individuals in a fourth, non\u2010consanguineous family were found to be compound heterozygous for two LGI4 missense mutations. It is not known how these missense mutations affect the biology of LGI4. Here we investigated whether these missense mutations affected the secretion of the protein, its ADAM22 binding capacity, or its myelination\u2010promoting function. We demonstrate that the mutations largely affect the progression of the mutant protein through the endomembrane system resulting in severely reduced expression. Importantly, binding to ADAM22 and myelination\u2010promoting activity appear largely unaffected, suggesting that treatment with chemical chaperones to improve secretion of the mutant proteins might prove beneficial.<\/jats:p>","DOI":"10.1002\/glia.24061","type":"journal-article","created":{"date-parts":[[2021,7,21]],"date-time":"2021-07-21T08:03:42Z","timestamp":1626854622000},"page":"2605-2617","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Characterizing the molecular etiology of arthrogryposis multiplex congenita in patients with <scp><i>LGI4<\/i><\/scp> mutations"],"prefix":"10.1002","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6216-2863","authenticated-orcid":false,"given":"Daniel G.","family":"Booth","sequence":"first","affiliation":[{"name":"Centre for Discovery Brain Sciences and MS Society Edinburgh Centre for MS Research University of Edinburgh  Edinburgh United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Kozar","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences and MS Society Edinburgh Centre for MS Research University of Edinburgh  Edinburgh United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen","family":"Bradley","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences and MS Society Edinburgh Centre for MS Research University of Edinburgh  Edinburgh United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8461-6341","authenticated-orcid":false,"given":"Dies","family":"Meijer","sequence":"additional","affiliation":[{"name":"Centre for Discovery Brain Sciences and MS Society Edinburgh Centre for MS Research University of Edinburgh  Edinburgh United Kingdom"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,7,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/0471142905.hg0720s76"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2008.09.006"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/nn1598"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1385\/NMM:8:1-2:191"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.4074"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1242\/bio.042085"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.92.16.7297"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1379\/1466-1268(1996)001<0117:CCCTMP>2.3.CO;2"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.11.4.1457"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23886"},{"key":"e_1_2_8_12_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3389\/fphar.2012.00137","article-title":"Molecular chaperones as targets to circumvent the CFTR defect in cystic fibrosis","volume":"3","author":"Chanoux R. A.","year":"2012","journal-title":"Frontiers in Pharmacology"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0046688"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.brainres.2016.03.046"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.4161\/pri.28938"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1227\/01.NEU.0000192363.84287.8B"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1152\/physrev.00010.2016"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.05.017"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1006376"},{"issue":"2","key":"e_1_2_8_20_1","first-page":"90","article-title":"The syndrome of arthrogryposis multiplex congenita","volume":"7","author":"Drachman D. B.","year":"1971","journal-title":"Birth Defects Original Article Series"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2017.07.012"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20320"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1055\/s-2008-1059546"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2014.03.008"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1159\/000446617"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1093\/oxfordjournals.jhered.a111088"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-444-63432-0.00011-6"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1009269107"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng832"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.305250.117"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1042\/AN20120095"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.107995"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2015.053"},{"key":"e_1_2_8_34_1","volume-title":"Cultering nerve cells","author":"Kleitman N.","year":"2002"},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt618"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1002\/bdra.20738"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2016.07.021"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.23578"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1997.8547"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmg.2019.103756"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2286-10.2010"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.6287-09.2010"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2015.04.014"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jviromet.2006.07.024"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2202-6-33"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20751"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbt.2014.01.002"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.109.6.3095"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13104-016-1915-8"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.2475211"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7862-5_9"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1002\/iub.1576"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.3389\/fnmol.2016.00162"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.23297"},{"key":"e_1_2_8_55_1","doi-asserted-by":"publisher","DOI":"10.1002\/glia.20390"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajhg.2017.02.006"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-03947-w"},{"key":"e_1_2_8_58_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3759"}],"container-title":["Glia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.24061","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/glia.24061","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/glia.24061","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T21:17:31Z","timestamp":1692825451000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/glia.24061"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,21]]},"references-count":57,"journal-issue":{"issue":"11","published-print":{"date-parts":[[2021,11]]}},"alternative-id":["10.1002\/glia.24061"],"URL":"https:\/\/doi.org\/10.1002\/glia.24061","archive":["Portico"],"relation":{},"ISSN":["0894-1491","1098-1136"],"issn-type":[{"value":"0894-1491","type":"print"},{"value":"1098-1136","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,21]]},"assertion":[{"value":"2020-06-01","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-09","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-07-21","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}