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, Shifengca
- dc.contributor.author Gut, Martaca
- dc.contributor.author Gut, Ivo Glynneca
- dc.contributor.author Melki, Judithca
- dc.date.accessioned 2018-05-14T07:47:39Z
- dc.date.available 2018-05-14T07:47:39Z
- dc.date.issued 2017
- 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.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.doi http://dx.doi.org/10.1016/j.ajhg.2017.02.006
- dc.identifier.issn 0002-9297
- dc.identifier.uri http://hdl.handle.net/10230/34622
- dc.language.iso eng
- dc.publisher Elsevierca
- 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.rights.accessRights info:eu-repo/semantics/openAccess
- 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.title Loss-of-function mutations in LGI4, a secreted ligand involved in schwann cell myelination, are responsible for arthrogryposis multiplex congenitaca
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion