Related Experiment Video
Updated: Apr 25, 2026
Induction and Micro-CT Imaging of Cerebral Cavernous Malformations in Mouse Model
Published on: September 4, 2017
Exceptional aggressiveness of cerebral cavernous malformation disease associated with PDCD10 mutations
Robert Shenkar1, Changbin Shi1, Tania Rebeiz2
1Neurovascular Surgery Program, Section of Neurosurgery, The University of Chicago Medicine, Chicago, IL 60637, USA.
Purpose:
The 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.
Methods:
We 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.
Results:
We 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.
Conclusion:
These 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.
Insights
Rare PDCD10 mutations cause aggressive cerebral cavernous malformation (CCM) with unique symptoms. This study links PDCD10 to Rho kinase activity and vascular permeability, offering therapeutic insights.
Area of Science:
- Genetics
- Vascular Biology
- Neurology
Background:
- Cerebral cavernous malformation (CCM) is a vascular disorder.
- PDCD10 mutations are rare causes of CCM.
- The clinical and mechanistic aspects of PDCD10-related CCM are poorly understood.
Purpose of the Study:
- To systematically examine the phenotypic manifestations of CCM caused by PDCD10 mutations.
- To establish a mechanistic link between PDCD10 mutations, Rho kinase (ROCK)-mediated hyperpermeability, and CCM.
- To identify potential therapeutic targets for PDCD10-related CCM.
Main Methods:
- In vitro analysis of PDCD10 small interfering RNA-treated endothelial cells for stress fibers, ROCK activity, and permeability.
- Assessment of ROCK activity in murine and human CCM lesions.
- Quantification of brain permeability and CCM lesion burden in PDCD10 mutation subjects.
- Evaluation of clinical manifestations in prospectively enrolled subjects.
Main Results:
- PDCD10 suppresses endothelial stress fibers, ROCK activity, and permeability in vitro.
- PDCD10 deficiency leads to increased lesion burden and vascular permeability in mice and humans.
- PDCD10-related CCM exhibits an exceptionally aggressive clinical phenotype, including early-onset disease, frequent hemorrhages, scoliosis, cognitive disability, and skin lesions.
- Robust ROCK activity was observed in CCM vasculature.
Conclusions:
- PDCD10 mutations define a unique and aggressive form of cerebral cavernous malformation.
- Findings highlight the role of Rho kinase-mediated hyperpermeability in PDCD10-related CCM.
- This research informs preclinical therapeutic strategies, clinical counseling, and trial design for PDCD10-related CCM.
More Related Videos
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
06:04Author Spotlight: Studying Clinical Characters and Epilepsy Outcomes After Frontal Disconnection in Patients with MOGHE
Published on: August 16, 2024
Related Concept Videos
01:24Parkinson Disease ll: Pathophysiology
01:24Parkinson Disease l: Introduction
01:22Cerebral Edema ll: Pathophysiology
01:29Cardiomyopathy III: Hypertrophic Cardiomyopathy
01:15Parkinson's Disease: Overview
01:21Huntington Disease l: Introduction