Article open access publication

De Novo Pathogenic Variants in CACNA1E Cause Developmental and Epileptic Encephalopathy with Contractures, Macrocephaly, and Dyskinesias

American Journal of Human Genetics, Elsevier, ISSN 1537-6605

Volume 103, 5, 2018

DOI:10.1016/j.ajhg.2018.09.006, Dimensions: pub.1107687855, PMC: PMC6216110, PMID: 30343943,

Authors

Zeng, Xue (13)
Zhu, Chang-Lian (16) (17)
Boysen, Katja E (18) (19)
Haan, Eric (22) (23)
Smith, Nicholas (23) (24)
Wang, Raymond (34) (35)
Sanchis-Juan, Alba (44) (45)
Carss, Keren J (44) (45)
Kerr, Bronwyn A (48) (49)
Banka, Siddharth (48) (49)
Scheffer, Ingrid Eileen (18) (19) (52) (53)
Helbig, Ingo (1) (54)

* Corresponding author

Affiliations

Organisations

  1. (1) Children's Hospital of Philadelphia, grid.239552.a
  2. (2) Hertie Institute for Clinical Brain Research, grid.428620.a
  3. (3) University of Calgary, grid.22072.35
  4. (4) University of Washington, grid.34477.33
  5. (5) APHP, Département de Génétique, Centre de Référence Déficiences Intellectuelles de Causes Rares, Groupe Hospitalier Pitié Salpêtrière et GHUEP Hôpital Trousseau; Sorbonne Université, GRC “Déficience Intellectuelle et Autisme,” 75013 Paris, France
  6. (6) Sorbonne University, grid.462844.8
  7. (7) Odense University Hospital, grid.7143.1, Southern Denmark Region
  8. (8) Radboud University Nijmegen Medical Centre, grid.10417.33
  9. (9) Stichting Epilepsie Instellingen Nederland, grid.419298.f
  10. (10) Kempenhaeghe, grid.479666.c
  11. (11) Barrow Neurological Institute, Phoenix Children’s Hospital, Departments of Child Health, Genetics, Neurology, and Cellular Molecular Medicine, University of Arizona College of Medicine, Phoenix, AZ 85013, USA
  12. (12) Phoenix Children's Hospital, grid.417276.1
  13. (13) Yale University, grid.47100.32
  14. (14) Penteli General Children's Hospital, grid.417205.5
  15. (15) Children's Hospital of Fudan University, grid.411333.7
  16. (16) University of Gothenburg, grid.8761.8
  17. (17) Zhengzhou University, grid.207374.5
  18. (18) Austin Health, grid.410678.c
  19. (19) University of Melbourne, grid.1008.9
  20. (20) Mayo Clinic, grid.66875.3a
  21. (21) University of Illinois at Peoria, grid.430852.8
  22. (22) Royal Adelaide Hospital, grid.416075.1
  23. (23) University of Adelaide, grid.1010.0
  24. (24) Women's and Children's Hospital, grid.1694.a
  25. (25) Duke University Hospital, grid.189509.c
  26. (26) CeGaT (Germany), grid.498061.2
  27. (27) University of Tübingen, grid.10392.39
  28. (28) Boston Children's Hospital, grid.2515.3
  29. (29) Harvard University, grid.38142.3c
  30. (30) Hackensack University Medical Center, grid.239835.6
  31. (31) University of Louisville, grid.266623.5
  32. (32) Children's Hospital of Wisconsin, grid.414086.f
  33. (33) University of Utah, grid.223827.e
  34. (34) Children's Hospital of Orange County, grid.414164.2
  35. (35) University of California, Irvine, grid.266093.8
  36. (36) University of Auckland, grid.9654.e
  37. (37) Starship Children's Health, grid.414054.0
  38. (38) University of Otago, grid.29980.3a
  39. (39) Karolinska University Hospital, grid.24381.3c
  40. (40) Karolinska Institute, grid.4714.6
  41. (41) University of Florence, grid.8404.8
  42. (42) Greenwood Genetic Center, grid.418307.9
  43. (43) Sanford Health, grid.490404.d
  44. (44) Cambridge University Hospitals NHS Foundation Trust, grid.24029.3d
  45. (45) University of Cambridge, grid.5335.0
  46. (46) Royal Devon & Exeter NHS Foundation Trust, grid.419309.6
  47. (47) Leeds Teaching Hospitals NHS Trust, grid.415967.8
  48. (48) St Mary's Hospital, grid.416523.7
  49. (49) University of Manchester, grid.5379.8
  50. (50) Royal Manchester Children's Hospital, grid.415910.8
  51. (51) Wellcome Sanger Institute, grid.10306.34
  52. (52) Murdoch Children's Research Institute, grid.1058.c
  53. (53) Royal Children's Hospital, grid.416107.5
  54. (54) Kiel University, grid.9764.c

Description

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders often beginning in infancy or early childhood that are characterized by intractable seizures, abundant epileptiform activity on EEG, and developmental impairment or regression. CACNA1E is highly expressed in the central nervous system and encodes the α1-subunit of the voltage-gated CaV2.3 channel, which conducts high voltage-activated R-type calcium currents that initiate synaptic transmission. Using next-generation sequencing techniques, we identified de novo CACNA1E variants in 30 individuals with DEE, characterized by refractory infantile-onset seizures, severe hypotonia, and profound developmental impairment, often with congenital contractures, macrocephaly, hyperkinetic movement disorders, and early death. Most of the 14, partially recurring, variants cluster within the cytoplasmic ends of all four S6 segments, which form the presumed CaV2.3 channel activation gate. Functional analysis of several S6 variants revealed consistent gain-of-function effects comprising facilitated voltage-dependent activation and slowed inactivation. Another variant located in the domain II S4-S5 linker results in facilitated activation and increased current density. Five participants achieved seizure freedom on the anti-epileptic drug topiramate, which blocks R-type calcium channels. We establish pathogenic variants in CACNA1E as a cause of DEEs and suggest facilitated R-type calcium currents as a disease mechanism for human epilepsy and developmental disorders.

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2018: Realized

Research area: Medicine

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2018: Level 2

Research area: Medicine

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Times Cited: 33

Field Citation Ratio (FCR): 12.2

Relative Citation ratio (RCR): 2.73

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