Cerebral cavernous malformations arise independent of the heart of glass receptor.

Abstract:

BACKGROUND AND PURPOSE:The Heart of Glass (HEG) receptor binds KRIT1 and functions with KRIT1, CCM2, and PDCD10 in a common signaling pathway required for heart and vascular development. Mutations in KRIT1, CCM2, and PDCD10 also underlie human cerebral cavernous malformation (CCM) and postnatal loss of these genes in the mouse endothelium results in rapid CCM formation. Here, we test the role of HEG in CCM formation in mice and in humans. METHODS:We constitutively or conditionally deleted Heg and Ccm2 genes in genetically modified mice. Mouse embryos, brain, and retina tissues were analyzed to assess CCM lesion formation. RESULTS:In postnatal mice, CCMs form with Ccm2-/- but not with Heg-/- or Heg-/-;Ccm2+/- endothelial cells. Consistent with these findings, human patients with CCM who lack exonic mutations in KRIT1, CCM2, or PDCD10 do not have mutations in HEG. CONCLUSIONS:These findings suggest that the HEG-CCM signaling functions during cardiovascular development and growth, whereas CCMs arise because of loss of HEG-independent CCM signaling in the endothelium of the central nervous system after birth.

journal_name

Stroke

journal_title

Stroke

authors

Zheng X,Riant F,Bergametti F,Myers CD,Tang AT,Kleaveland B,Pan W,Yang J,Tournier-Lasserve E,Kahn ML

doi

10.1161/STROKEAHA.114.004809

subject

Has Abstract

pub_date

2014-05-01 00:00:00

pages

1505-1509

issue

5

eissn

0039-2499

issn

1524-4628

journal_volume

45

pub_type

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