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.