Mutations in Apoptosis-related Gene, PDCD10, Cause Cerebral Cavernous Malformation 3

Güçlü, Bülent; Öztürk, Ali; Pricola, Katie L.; Bilgüvar, Kaya; Shin, Dana; O’Roak, Brian J.; Günel, Murat

doi:10.1227/01.neu.0000180811.56157.e1

Cited by 83 publications

(65 citation statements)

References 29 publications

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“…8) and was identified previously as an interactor for the GCKIII proteins (9,10). CCMs are vascular lesions of the brain characterized by enlarged capillaries that lack structural integrity and that form caverns that tend to bleed, leading to symptoms ranging from headaches and dizziness to severe strokes and death (reviewed in Ref.…”

Section: Pp2amentioning

confidence: 99%

Structure-Function Analysis of Core STRIPAK Proteins

Kean

Ceccarelli

Goudreault

et al. 2011

Journal of Biological Chemistry

137

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We show that striatins and CCM3 regulate the Golgi localization of MST4 in an opposite manner. Consistent with a previously described function for MST4 and CCM3 in Golgi positioning, depletion of CCM3 or striatins affects Golgi polarization, also in an opposite manner. We propose that STRIPAK regulates the balance between MST4 localization at the Golgi and in the cytosol to control Golgi positioning.

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Section: Pp2amentioning

confidence: 99%

Structure-Function Analysis of Core STRIPAK Proteins

Kean

Ceccarelli

Goudreault

et al. 2011

Journal of Biological Chemistry

137

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“…A majority of mutations in CCM genes result in truncations of their protein products, CCM1 (Krev/Rap1 Interacting Trapped 1; KRIT1) (3, 4), CCM2 (malcavernin, MGC4607, osmosensing scaffold for mitogen-activated protein kinase kinase kinase-3; OSM) (5, 6), and CCM3 (programmed cell death 10; PDCD10, TF-1 cell apoptosis-related protein 15; TFAR15) (7,8). These mutations are inherited in an autosomal dominant fashion (9) with acquisition of CCM lesions hypothesized to be due to a two-hit mechanism (10 -12).…”

Section: Cerebral Cavernous Malformation (Ccm)mentioning

confidence: 99%

Crystal Structure of CCM3, a Cerebral Cavernous Malformation Protein Critical for Vascular Integrity

Zhang

et al. 2010

Journal of Biological Chemistry

117

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CCM3 mutations are associated with cerebral cavernous malformation (CCM), a disease affecting 0.1-0.5% of the human population. CCM3 (PDCD10, TFAR15) is thought to form a CCM complex with CCM1 and CCM2; however, the molecular basis for these interactions is not known. We have determined the 2.5 Å crystal structure of CCM3. This structure shows an all ␣-helical protein containing two domains, an N-terminal dimerization domain with a fold not previously observed, and a C-terminal focal adhesion targeting (FAT)-homology domain. We show that CCM3 binds CCM2 via this FAThomology domain and that mutation of a highly conserved FAK-like hydrophobic pocket (HP1) abrogates CCM3-CCM2 interaction. This CCM3 FAT-homology domain also interacts with paxillin LD motifs using the same surface, and partial CCM3 co-localization with paxillin in cells is lost on HP1 mutation. Disease-related CCM3 truncations affect the FAT-homology domain suggesting a role for the FAT-homology domain in the etiology of CCM. Cerebral cavernous malformation (CCM)4 is a common vascular lesion that affects the central nervous system vasculature with a prevalence of 0.1-0.5% in the human population (1, 2) (OMIM 116860, 603284, 603285). CCMs manifest as thinwalled, dilated blood vessels lined by a monolayer of endothelial cells that lack tight junctions. The clinical effects of these lesions include seizures, headaches, and stroke in midlife and are often associated with focal hemorrhage (1, 2). These lesions can occur sporadically or as a familial form attributable to mutations in three different genes: CCM1, CCM2, and CCM3.A majority of mutations in CCM genes result in truncations of their protein products, CCM1 (Krev/Rap1 Interacting Trapped 1; KRIT1) (3, 4), CCM2 (malcavernin, MGC4607, osmosensing scaffold for mitogen-activated protein kinase kinase kinase-3; OSM) (5, 6), and CCM3 (programmed cell death 10; PDCD10, TF-1 cell apoptosis-related protein 15; TFAR15) (7,8). These mutations are inherited in an autosomal dominant fashion (9) with acquisition of CCM lesions hypothesized to be due to a two-hit mechanism (10 -12). Expression of the CCM proteins is required for both development and maintenance of endothelial cells in the vasculature; they are required for normal vasculogenesis (13) and global deletion of CCM1 renders mice nonviable (14), a result also seen in global or endothelial-specific deletion of CCM2 (15) and CCM3 (16). Overall, the clinical and in vivo data point to an essential role for the CCM proteins in endothelial cells that makes them critical for vasculogenesis and survival.CCM1, CCM2, and CCM3 interact with one another and play roles in multiple signaling pathways with CCM2 acting as a hub that directly interacts with both CCM3 (17) and CCM1 (18,19). The structural characteristics of the CCM proteins have not been directly assessed but have been inferred by molecular modeling and homology studies that suggest three regions in CCM1 (NPXY-rich, ankyrin repeat, and FERM domains) (20) and a predicted phosphotyrosine binding (PTB) dom...

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“…Familial CCMs are inherited in an autosomal dominant pattern, constitute up to 50% of CCM cases, and have been found to be associated with loss-of-function mutations in 3 genes, KRIT1 (also known as CCM1) (1)(2)(3), CCM2 (MALCAVERNIN, OSM) (4,5), and PDCD10 (CCM3) (6,7). Genetic studies in zebrafish have demonstrated that loss of ccm1, ccm2, or the transmembrane receptor heart of glass (heg) results in embryonic cardiovascular phenotypes characterized by a large, thin-walled heart and defective branchial arch artery development that prevents blood circulation (8)(9)(10).…”

Section: Introductionmentioning

confidence: 99%

CCM3 signaling through sterile 20–like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations

Zheng¹,

Xu²,

Lorenzo³

et al. 2010

J. Clin. Invest.

139

199

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Mutations in Apoptosis-related Gene, PDCD10, Cause Cerebral Cavernous Malformation 3

Abstract: Our data establish PDCD10 as the gene responsible for CCM in families linking to the CCM3 locus. The discovery of the third gene involved in inherited forms of CCM, after KRIT1 and Malcavernin, is an important step toward dissecting the molecular pathophysiology of this disease.

Cited by 83 publications

References 29 publications

Structure-Function Analysis of Core STRIPAK Proteins

Structure-Function Analysis of Core STRIPAK Proteins

Crystal Structure of CCM3, a Cerebral Cavernous Malformation Protein Critical for Vascular Integrity

CCM3 signaling through sterile 20–like kinases plays an essential role during zebrafish cardiovascular development and cerebral cavernous malformations

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