De novo stop-loss variants in CLDN11 cause hypomyelinating leukodystrophy

Brain. 2021 Mar 3;144(2):411-419. doi: 10.1093/brain/awaa410.

Korbinian M Riedhammer ¹ ², Sylvia Stockler ³, Rafal Ploski ⁴, Maren Wenzel ⁵, Burkhard Adis-Dutschmann ⁶, Uwe Ahting ¹, Bader Alhaddad ¹, Astrid Blaschek ⁷, Tobias B Haack ¹ ⁸, Robert Kopajtich ¹ ⁹, Jessica Lee ¹⁰, Victor Murcia Pienkowski ⁴, Agnieszka Pollak ⁴, Krystyna Szymanska ¹¹, Maja Tarailo-Graovac ¹² ¹³, Robin van der Lee ¹⁰, Clara D van Karnebeek ¹⁰ ¹⁴, Thomas Meitinger ¹, Ingeborg Krägeloh-Mann ¹⁵, Katharina Vill ⁷

Affiliations

1 Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, 81675, Germany.
2 Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, Munich, 81675, Germany.
3 Division of Biochemical Diseases, Department of Pediatrics, B.C. Children's Hospital, The University of British Columbia, Vancouver, BC V6H 0B3, Canada.
4 Department of Medical Genetics, Medical University of Warsaw, Warsaw, 02-106, Poland.
5 Genetikum, Genetic Counseling and Diagnostics, Neu-Ulm, 89231, Germany.
6 Center for Pediatrics, Ulm, 89073, Germany.
7 Dr. v. Hauner Children's Hospital, Department of Pediatric Neurology and Developmental Medicine, LMU - University of Munich, 80337, Germany.
8 Institute of Medical Genetics and Applied Genomics, University of Tübingen, 72076 Tübingen, Germany.
9 Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, 85764, Germany.
10 Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, Department of Medical Genetics and Pediatrics, The University of British Columbia, Vancouver, BC V6H 0B3, Canada.
11 Department of Experimental and Clinical Neuropathology, Mossakowski Medical Research Center, Polish Academy of Sciences, Warsaw, 02-106, Poland.
12 Department of Medical Genetics, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
13 Department of Biochemistry and Molecular Biology, Alberta Children's Hospital Research Institute, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada.
14 Department of Pediatric Metabolic Diseases, Amalia Children's Hospital, Radboud University Medical centre, Nijmegen, 6525 GA, The Netherlands.
15 Department of Pediatric Neurology and Developmental Medicine, University Children's Hospital, Tübingen, 72076, Germany.

PMID: 33313762 DOI: 10.1093/brain/awaa410

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.

Keywords

CLDN11; exome; hypomyelinating leukodystrophy; stop-loss; tight junction.

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