<i>De novo</i> stop-loss variants in <i>CLDN11</i> cause hypomyelinating leukodystrophy
Korbinian M. Riedhammer, Sylvia Stöckler, Rafał Płoski, Maren Wenzel, Burkhard Adis-Dutschmann, Uwe Ahting, Bader Alhaddad, Astrid Blaschek, Tobias B. Haack, Robert Kopajtich, Jessica Lee, Victor Murcia Pienkowski, Agnieszka Pollak, Krystyna Szymańska, Maja Tarailo‐Graovac, Robin van der Lee, Clara D.M. van Karnebeek, Thomas Meitinger, Ingeborg Krägeloh‐Mann, Katharina Vill
Abstract
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.