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Riedhammer, K.M.* ; Stockler, S.* ; Ploski, R.* ; Wenzel, M.* ; Adis-Dutschmann, B.* ; Ahting, U.* ; Alhaddad, B.* ; Blaschek, A.* ; Haack, T.B.* ; Kopajtich, R. ; Lee, J.Y.* ; Murcia Pienkowski, V.* ; Pollak, A.* ; Szymanska, K.* ; van der Lee, R.* ; van Karnebeek, C.D.M.* ; Meitinger, T.* ; Krägeloh-Mann, I.* ; Vill, K.*

De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy.

Brain 144, 411-419 (2021)
Publ. Version/Full Text Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
Claudin-11, a tight junction protein, is indispensable in the formation of the radial component of myelin. Here, we report de novo stop-loss variants in the gene encoding claudin-11, CLDN11, in three unrelated individuals presenting with an early-onset spastic movement disorder, expressive speech disorder and eye abnormalities including hypermetropia. Brain MRI showed a myelin deficit with a discrepancy between T1-weighted and T2-weighted images and some progress in myelination especially involving the central and peripheral white matter. Exome sequencing identified heterozygous stop-loss variants c.622T>C, p.(*208Glnext*39) in two individuals and c.622T>G, p.(*208Gluext*39) in one individual, all occurring de novo. At the RNA level, the variant c.622T>C did not lead to a loss of expression in fibroblasts, indicating this transcript is not subject to nonsense-mediated decay and most likely translated into an extended protein. Extended claudin-11 is predicted to form an alpha helix not incorporated into the cytoplasmic membrane, possibly perturbing its interaction with intracellular proteins. Our observations suggest that stop-loss variants in CLDN11 expand the genetically heterogeneous spectrum of hypomyelinating leukodystrophies.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Cldn11 ; Exome ; Hypomyelinating Leukodystrophy ; Stop-loss ; Tight Junction; Cns Myelin; Tight Junctions; Pep-fold; Osp/claudin-11; Complex; Absence; Forms
ISSN (print) / ISBN 0006-8950
e-ISSN 1460-2156
Journal Brain: A Journal of Neurology
Quellenangaben Volume: 144, Issue: 2, Pages: 411-419 Article Number: , Supplement: ,
Publisher Oxford University Press
Publishing Place Great Clarendon St, Oxford Ox2 6dp, England
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants German Network for Mitochondrial Disorders (mitoNET)
intramural fortune program
Deutsche Forschungsgemeinschaft (DFG, German Research foundation)
Canadian Institutes of Health Research
National Ataxia Foundation
Genome British Columbia
Genome Canada (ABC4DE Project)
Michael Smith Foundation for Health Foundation Research Scholar Award
Foundation Metakids salary award
Rubicon fellowship from the Netherlands Organization for Scientific Research (NWO and ZONMW)
German Bundesministerium fur Bildung und Forschung (BMBF) through the Juniorverbund in der Systemmedizin "mitOmics"