NDLI: Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

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Pathomechanistic characterization of two exonic L1CAM variants located in trans in an obligate carrier of X-linked hydrocephalus

Content Provider	Springer Nature Link
Author	Marx, Mariola Diestel, Simone Bozon, Muriel Keglowich, Laura Drouot, Nathalie Bouché, Elisabeth Frebourg, Thierry Minz, Marie Saugier Veber, Pascale Castellani, Valérie Schäfer, Michael K. E.
Copyright Year	2011
Abstract	Mutations in the gene encoding the neural cell adhesion molecule L1CAM cause several neurological disorders collectively referred to as L1 syndrome. We report here a family case of X-linked hydrocephalus in which an obligate female carrier has two exonic L1CAM missense mutations in trans substituting amino acids in the first (p.W635C) or second (p.V768I) fibronectin-type III domains. We performed various biochemical and cell biological in vitro assays to evaluate the pathogenicity of these variants. Mutant L1-W635C protein accumulates in the endoplasmic reticulum (ER), is not transported into axons, and fails to promote L1CAM-mediated cell–cell adhesion as well as neurite growth. Immunoprecipitation experiments show that L1-W635C associates with the molecular ER chaperone calnexin and is modified by poly-ubiquitination. The mutant L1-V768I protein localizes at the cell surface, is not retained in the ER, and promotes neurite growth similar to wild-type L1CAM. However, the p.V768I mutation impairs L1CAM-mediated cell–cell adhesion albeit less severe than L1-W635C. These data indicate that p.W635C is a novel loss-of-function L1 syndrome mutation. The p.V768I mutation may represent a non-pathogenic variant or a variant associated with low penetrance. The poly-ubiquitination of L1-W635C and its association with the ER chaperone calnexin provide further insights into the molecular mechanisms underlying defective cell surface trafficking of L1CAM in L1 syndrome.
Starting Page	49
Ending Page	59
Page Count	11
File Format	PDF
ISSN	13646745
Journal	Neurogenetics
Volume Number	13
Issue Number	1
e-ISSN	13646753
Language	English
Publisher	Springer-Verlag
Publisher Date	2012-01-06
Publisher Place	Berlin, Heidelberg
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	L1CAM X-linked hydrocephalus Neurite growth Protein trafficking ER retention Ubiquitin-proteasome system Molecular Medicine Neurosciences Human Genetics
Content Type	Text
Resource Type	Article
Subject	Genetics Cellular and Molecular Neuroscience Genetics (clinical)

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