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

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. © The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Citation

Korbinian M Riedhammer, Sylvia Stockler, Rafal Ploski, Maren Wenzel, Burkhard Adis-Dutschmann, Uwe Ahting, Bader Alhaddad, Astrid Blaschek, Tobias B Haack, Robert Kopajtich, Jessica Lee, Victor Murcia Pienkowski, Agnieszka Pollak, Krystyna Szymanska, Maja Tarailo-Graovac, Robin van der Lee, Clara D van Karnebeek, Thomas Meitinger, Ingeborg Krägeloh-Mann, Katharina Vill. De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy. Brain : a journal of neurology. 2021 Mar 03;144(2):411-419

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PMID: 33313762

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