التفاصيل البيبلوغرافية
| العنوان: |
Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations |
| المؤلفون: |
Shenkar, Robert, Shi, Changbin, Rebeiz, Tania, Stockton, Rebecca A, McDonald, David A, Mikati, Abdul Ghani, Zhang, Lingjiao, Austin, Cecilia, Akers, Amy L, Gallione, Carol J, Rorrer, Autumn, Gunel, Murat, Min, Wang, Marcondes de Souza, Jorge, Lee, Connie, Marchuk, Douglas A, Awad, Issam A |
| المصدر: |
Genetics in Medicine, vol 17, iss 3 |
| بيانات النشر: |
eScholarship, University of California |
| سنة النشر: |
2015 |
| المجموعة: |
University of California: eScholarship |
| مصطلحات موضوعية: |
Neurosciences, Rare Diseases, Brain Disorders, Development of treatments and therapeutic interventions, Aetiology, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine, Adolescent, Adult, Animals, Apoptosis Regulatory Proteins, Carrier Proteins, Cells, Cultured, Central Nervous System Neoplasms, Child, Preschool, Disease Models, Animal, Hemangioma, Cavernous, Central Nervous System, Human Umbilical Vein Endothelial Cells, Humans, Infant, Intracellular Signaling Peptides and Proteins, Keratin-1, Membrane Proteins, Mice |
| جغرافية الموضوع: |
188 - 196 |
| الوصف: |
PurposeThe phenotypic manifestations of cerebral cavernous malformation disease caused by rare PDCD10 mutations have not been systematically examined, and a mechanistic link to Rho kinase-mediated hyperpermeability, a potential therapeutic target, has not been established.MethodsWe analyzed PDCD10 small interfering RNA-treated endothelial cells for stress fibers, Rho kinase activity, and permeability. Rho kinase activity was assessed in cerebral cavernous malformation lesions. Brain permeability and cerebral cavernous malformation lesion burden were quantified, and clinical manifestations were assessed in prospectively enrolled subjects with PDCD10 mutations.ResultsWe determined that PDCD10 protein suppresses endothelial stress fibers, Rho kinase activity, and permeability in vitro. Pdcd10 heterozygous mice have greater lesion burden than other Ccm genotypes. We demonstrated robust Rho kinase activity in murine and human cerebral cavernous malformation vasculature and increased brain vascular permeability in humans with PDCD10 mutation. Clinical phenotype is exceptionally aggressive compared with the more common KRIT1 and CCM2 familial and sporadic cerebral cavernous malformation, with greater lesion burden and more frequent hemorrhages earlier in life. We first report other phenotypic features, including scoliosis, cognitive disability, and skin lesions, unrelated to lesion burden or bleeding.ConclusionThese findings define a unique cerebral cavernous malformation disease with exceptional aggressiveness, and they inform preclinical therapeutic testing, clinical counseling, and the design of trials.Genet Med 17 3, 188-196. |
| نوع الوثيقة: |
article in journal/newspaper |
| وصف الملف: |
application/pdf |
| اللغة: |
unknown |
| العلاقة: |
qt0cs6m4h5; https://escholarship.org/uc/item/0cs6m4h5Test |
| الإتاحة: |
https://escholarship.org/uc/item/0cs6m4h5Test |
| حقوق: |
public |
| رقم الانضمام: |
edsbas.AF0B16B1 |
| قاعدة البيانات: |
BASE |
