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Novel CCM2 missense variants abrogating the CCM1–CCM2 interaction cause cerebral cavernous malformations
  1. Françoise Bergametti1,
  2. Geraldine Viot2,
  3. Christophe Verny3,
  4. Marie Pierre Brechard4,
  5. Christian Denier5,
  6. Pierre Labauge6,
  7. Paul Petit7,
  8. Aurélien Nouet8,
  9. François Viallet9,
  10. Annabelle Chaussenot10,
  11. Dominique Hervé11,12,
  12. Elisabeth Tournier-Lasserve1,12,13,
  13. Florence Riant1,12,13
  1. 1UMR-S1141, INSERM, Paris, Île-de-France, France
  2. 2Unité de Génétique, Hopital Americain de Paris, Neuilly-sur-Seine, Île-de-France, France
  3. 3Service de Neurologie, CHU Angers, Angers, Pays de la Loire, France
  4. 4Service de Génétique Médicale, Hopital Saint Joseph, Marseille, Provence-Alpes-Côte d'Azur, France
  5. 5Département de Neurologie, Hospital Bicetre, Le Kremlin-Bicetre, Île-de-France, France
  6. 6Service de Neurologie, CHRU de Montpellier, Montpellier, Languedoc-Roussillon, France
  7. 7Cabinet de Neurologie - Cabestan, Cabestan, France
  8. 8Service de Neurochirurgie, Hopital Universitaire Pitie Salpetriere, Paris, Île-de-France, France
  9. 9Service de Neurologie, CH intercommunal Aix-Pertuis, Aix en Provence, France
  10. 10Service de Génétique Médicale, Hopital de l'Archet, Nice, Provence-Alpes-Côte d'Azur, France
  11. 11Service de Neurologie, GH Saint Louis - Lariboisiere - Fernand Widal, Paris, Île-de-France, France
  12. 12Centre de Référence pour les Maladies Rares des Vaisseaux du Cerveau et de l'Oeil (CERVCO), GH Saint Louis - Lariboisiere - Fernand Widal, Paris, Île-de-France, France
  13. 13Service de Génétique Moléculaire Neurovasculaire, GH Saint Louis - Lariboisière - Fernand Widal, Paris, Île-de-France, France
  1. Correspondence to Dr Florence Riant, Service de Génétique Moléculaire Neurovasculaire, GH Lariboisiere Fernand-Widal, Paris 75010, France; florence.riant{at}


Background Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three CCM genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few CCM2 missense variants have been shown to be deleterious by modifying the ternary CCM complex stability.

Objectives To investigate the causality of novel missense CCM2 variants detected in patients with CCM.

Methods The three CCM genes were screened in 984 patients referred for CCM molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the CCM2 missense variants located in the phosphotyrosine binding (PTB) domain.

Results 11 distinct CCM2 rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a loss of interaction between CCM1 and CCM2 was observed for all six variants.

Conclusion We showed, using co-immunoprecipitation experiments, that CCM2 missense variants located in the PTB domain were actually damaging by preventing the normal interaction between CCM1 and CCM2. These data are important for diagnosis and genetic counselling, which are challenging in patients harbouring such variants.

  • cerebral cavernous malformation
  • CCM
  • CCM2
  • PTB domain
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  • Contributors FR and ETL designed the study, FR performed the genetic analyses, FB performed the co-immunoprecipitation experiments, FR and FB wrote the manuscript, GV, CV, MPB, CD, PL, PP, AN, FV, AC and DH provided clinical and neuroimaging data, ETL revised the manuscript critically for important intellectual content, FR submitted the study and is responsible for the overall content as guarantor.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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