Journal article
Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice
The Journal of clinical investigation, Vol.121(5), pp.1871-1881
05/01/2011
DOI: 10.1172/JCI44393
PMCID: PMC3083782
PMID: 21490399
Abstract
Cerebral cavernous malformations (CCMs) are a common type of vascular malformation in the brain that are a major cause of hemorrhagic stroke. This condition has been independently linked to 3 separate genes: Krevl interaction trapped (KRIT1), Cerebral cavernous malformation 2 (CCM2), and Programmed cell death 10 (PDCD10). Despite the commonality in disease pathology caused by mutations in these 3 genes, we found that the loss of Pdcd10 results in significantly different developmental, cell biological, and signaling phenotypes from those seen in the absence of Ccm2 and Kritl. PDCD10 bound to germinal center kinase III (GCKIH) family members, a subset of serine-threonine kinases, and facilitated lumen formation by endothelial cells both in vivo and in vitro. These findings suggest that CCM may be a common tissue manifestation of distinct mechanistic pathways. Nevertheless, loss of heterozygosity (LOH) for either Pdcdl 0 or Ccm2 resulted in CCMs in mice. The murine phenotype induced by loss of either protein reproduced all of the key clinical features observed in human patients with CCM, as determined by direct comparison with genotype-specific human surgical specimens. These results suggest that CCM may be more effectively treated by directing therapies based on the underlying genetic mutation rather than treating the condition as a single clinical entity.
Details
- Title: Subtitle
- Mutations in 2 distinct genetic pathways result in cerebral cavernous malformations in mice
- Creators
- Aubrey C. Chan - University of UtahStavros G. Drakos - University of UtahOscar E. Ruiz - University of UtahAlexandra C. H. Smith - University of UtahChristopher C. Gibson - University of UtahJing Ling - University of UtahSamuel F. Passi - University of UtahAmber N. Stratman - University of MissouriAnastasia Sacharidou - University of MissouriM. Patricia Revelo - University of UtahAllie H. Grossmann - University of UtahNikolaos A. Diakos - University of UtahGeorge E. Davis - University of MissouriMark M. Metzstein - University of UtahKevin J. Whitehead - University of UtahDean Y. Li - University of Utah
- Resource Type
- Journal article
- Publication Details
- The Journal of clinical investigation, Vol.121(5), pp.1871-1881
- Publisher
- Amer Soc Clinical Investigation Inc
- DOI
- 10.1172/JCI44393
- PMID
- 21490399
- PMCID
- PMC3083782
- ISSN
- 0021-9738
- eISSN
- 1558-8238
- Number of pages
- 11
- Grant note
- T32GM007464 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Edna Benning Foundation American Heart Association Juvenile Diabetes Research Foundation Hellenic Cardiological Society H.A. T32-GM007464 / US NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Burroughs Wellcome Fund R01HL059373 / NATIONAL HEART, LUNG, AND BLOOD INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI)
- Language
- English
- Date published
- 05/01/2011
- Academic Unit
- Psychiatry; Internal Medicine
- Record Identifier
- 9984280840602771
Metrics
9 Record Views