Variants in CLDN5 cause a syndrome characterized by seizures, microcephaly and brain calcifications

Author:

Deshwar Ashish R12ORCID,Cytrynbaum Cheryl12ORCID,Murthy Harsha2,Zon Jessica2,Chitayat David1,Volpatti Jonathan2,Newbury-Ecob Ruth3,Ellard Sian4,Allen Hana Lango5,Yu Emily P6,Noche Ramil6,Walker Suzi7,Scherer Stephen W27ORCID,Mahida Sonal8,Elitt Christopher M91011,Nicolas Gaël12ORCID,Goldenberg Alice12,Saugier-Veber Pascale12,Lecoquierre Francois12,Dabaj Ivana13ORCID,Meddaugh Hannah14,Marble Michael1415,Keppler-Noreuil Kim M16,Drayson Lucy17,Barañano Kristin W18,Chassevent Anna19,Agre Katie20,Létard Pascaline21,Bilan Frederic2122,Le Guyader Gwenaël2122,Laquerrière Annie23,Ramsey Keri24,Henderson Lindsay25,Brady Lauren26,Tarnopolsky Mark26,Bainbridge Matthew27,Friedman Jennifer272829,Capri Yline30,Athayde Larissa31,Kok Fernando31,Gurgel-Giannetti Juliana32,Ramos Luiza L P31,Blaser Susan33,Dowling James J23435ORCID,Weksberg Rosanna123536

Affiliation:

1. Division of Clinical and Metabolic Genetics, The Hospital for Sick Children , Toronto, ON M5G 1X8 , Canada

2. Genetics and Genome Biology, Research Institute, The Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada

3. Department of Clinical Genetics, University Hospitals Bristol NHS Foundation Trust , Bristol, BS2 8EG , UK

4. Molecular Genetics, Royal Devon & Exeter NHS Foundation Trust , Exeter, EX2 5DW , UK

5. MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge , Cambridge, CB2 0SL , UK

6. Zebrafish Genetics and Disease Models Core Facility, The Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada

7. The Centre for Applied Genomics, Genetics, and Genome Biology, The Hospital for Sick Children , Toronto, ON M5G 0A4 , Canada

8. Epilepsy Genetics Program, Department of Neurology, Boston Children’s Hospital , Boston, MA 02115 , USA

9. Fetal-Neonatal Neurology Program, Department of Neurology, Boston Children’s Hospital , Boston, MA 02115 , USA

10. F.M. Kirby Neurobiology Center, Boston Children’s Hospital , Boston, MA 02115 , USA

11. Department of Neurology, Harvard Medical School , Boston, MA 02115 , USA

12. Department of Genetics and Reference Center for Developmental Disorders, Normandy Center for Genomic and Personalized Medicine, UNIROUEN, INSERM U1245 and Rouen University Hospital, Normandie University , F 76000 Rouen , France

13. Department of Neonatology and Pediatric Intensive Care-Pediatric Neurology, Rouen University Hospital, and INSERM U1245, Normandie University, UNIROUEN , 76000 Rouen , France

14. Department of Genetics, Children’s Hospital of New Orleans , New Orleans, LA 70118 , USA

15. Department of Pediatrics, Louisiana State University Health Sciences Center , New Orleans, LA 70112 , USA

16. Department of Pediatrics, University of Wisconsin–Madison , Madison, WI 53792 , USA

17. Pediatric Specialists of Virginia , Fairfax, VA 22031 , USA

18. Department of Neurology, Johns Hopkins University School of Medicine , Baltimore, MA 21287 , USA

19. Division of Neurogenetics, Kennedy Krieger Institute , Baltimore, MA 21205 , USA

20. Department of Clinical Genomics, Mayo Clinic , Rochester, NY 55905 , USA

21. Department of Clinical Genetics, Service de Génétique, CHU de Poitiers , CS 90577 - 86021 Poitiers Cedex , France

22. EA3808 NEUVACOD, University of Poitiers , 86073 Poitiers , France

23. Department of Pathology, Normandy Centre for Genomic and Personalized Medicine, Normandie Univeristy, UNIROUEN, INSERM U1245 and Rouen University Hospital , F76000 Rouen , France

24. Translational Genomics Research Institute, Center for Rare Childhood Disorders , Phoenix, AZ 85004 , USA

25. GeneDx , Gaithersburg, MD 20877 , USA

26. Department of Pediatrics, McMaster University , Hamilton, ON L8S 4K1 , Canada

27. Rady Children’s Institute for Genomic Medicine , San Diego, CA 92123 , USA

28. Department of Neurosciences, University of California San Diego , San Diego, CA 92093 , USA

29. Department of Pediatrics, University of California San Diego , San Diego, CA 92093 , USA

30. Département de Génétique, Assistance Publique des Hôpitaux de Paris (AP-HP) Hôpital Robert Debré , 75019 Paris , France

31. Mendelics Genomic Analysis , Sao Paulo CEP 02511-000 , Brazil

32. Department of Pediatrics, Federal University of Minas Gerais School of Medicine , Belo Horizonte - MG - CEP 31270-901 , Brazil

33. Department of Diagnostic Imaging, The Hospital for Sick Children , Toronto, ON M5G 1X8 , Canada

34. Division of Neurology, The Hospital for Sick Children , Toronto, ON M5G1X8 , Canada

35. Department of Molecular Genetics, Faculty of Medicine, University of Toronto , Toronto, ON M5S 1A8 , Canada

36. Institutes of Medical Sciences, University of Toronto , Toronto, ON M5S 1A8 , Canada

Abstract

Abstract The blood–brain barrier ensures CNS homeostasis and protection from injury. Claudin-5 (CLDN5), an important component of tight junctions, is critical for the integrity of the blood–brain barrier. We have identified de novo heterozygous missense variants in CLDN5 in 15 unrelated patients who presented with a shared constellation of features including developmental delay, seizures (primarily infantile onset focal epilepsy), microcephaly and a recognizable pattern of pontine atrophy and brain calcifications. All variants clustered in one subregion/domain of the CLDN5 gene and the recurrent variants demonstrate genotype–phenotype correlations. We modelled both patient variants and loss of function alleles in the zebrafish to show that the variants analogous to those in patients probably result in a novel aberrant function in CLDN5. In total, human patient and zebrafish data provide parallel evidence that pathogenic sequence variants in CLDN5 cause a novel neurodevelopmental disorder involving disruption of the blood–brain barrier and impaired neuronal function.

Funder

Rare Diseases Models and Mechanisms Network

Recherche Innovation Normandie

European Regional Development Fund

European Reference Network for Developmental Anomalies and Intellectual Disability

Publisher

Oxford University Press (OUP)

Subject

Neurology (clinical)

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