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Loss-of-function mutations in LGI4, a secreted ligand involved in schwann cell myelination, are responsible for arthrogryposis multiplex congenita

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dc.contributor.author Xue, Shifeng
dc.contributor.author Gut, Marta
dc.contributor.author Gut, Ivo Glynne
dc.contributor.author Melki, Judith
dc.date.accessioned 2018-05-14T07:47:39Z
dc.date.available 2018-05-14T07:47:39Z
dc.date.issued 2017
dc.identifier.citation Xue S, Maluenda J, Marguet F, Shboul M, Quevarec L, Bonnard C et al. Loss-of-Function Mutations in LGI4 , a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita. Am J Hum Genet. 2017 Apr;100(4):659-65. DOI: 10.1016/j.ajhg.2017.02.006
dc.identifier.issn 0002-9297
dc.identifier.uri http://hdl.handle.net/10230/34622
dc.description.abstract Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through genetic mapping of disease loci and whole-exome sequencing in four unrelated multiplex families presenting with severe AMC, we identified biallelic loss-of-function mutations in LGI4 (leucine-rich glioma-inactivated 4). LGI4 is a ligand secreted by Schwann cells that regulates peripheral nerve myelination via its cognate receptor ADAM22 expressed by neurons. Immunolabeling experiments and transmission electron microscopy of the sciatic nerve from one of the affected individuals revealed a lack of myelin. Functional tests using affected individual-derived iPSCs showed that these germline mutations caused aberrant splicing of the endogenous LGI4 transcript and in a cell-based assay impaired the secretion of truncated LGI4 protein. This is consistent with previous studies reporting arthrogryposis in Lgi4-deficient mice due to peripheral hypomyelination. This study adds to the recent reports implicating defective axoglial function as a key cause of AMC.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher Elsevier
dc.relation.ispartof American Journal of Human Genetics. 2017 Apr;100(4):659-65
dc.rights © Elsevier This is the published version of an article http://dx.doi.org/10.1016/j.ajhg.2017.02.006 that appeared in the journal Am J Hum Genet. It is published in an Open Archive under an Elsevier user license. Details of this licence are available here: https://www.elsevier.com/about/our-business/policies/open-access-licenses/elsevier-user-license
dc.title Loss-of-function mutations in LGI4, a secreted ligand involved in schwann cell myelination, are responsible for arthrogryposis multiplex congenita
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1016/j.ajhg.2017.02.006
dc.subject.keyword ADAM22
dc.subject.keyword LGI4
dc.subject.keyword Schwann cells
dc.subject.keyword Arthrogryposis multiplex congenital
dc.subject.keyword Hypomyelination
dc.subject.keyword Secreted ligand
dc.subject.keyword Whole-exome sequencing
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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