Detection of Novel Mutation in Ccm3 Causes Familial Cerebral Cavernous Malformations

Scimone, Concetta; Bramantı, Placido; Ruggeri, Alessia; Katsarou, Zoe; Donato, Luigi; Sidoti, Antonina; D’Angelo, Rosalia

doi:10.1007/s12031-015-0606-6

Cited by 28 publications

(17 citation statements)

References 17 publications

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“…These above collective findings suggest that both Rosi and ROCK-i may be suitable candidates for changing TGF-β profibrotic signaling into pro-migratory BMP, resulting in the facilitation of the cell migration that is required for wound healing of conjunctiva. Furthermore, these observations also provide significant insights into other pathologies in which the TGF-β pathway and the role of the extracellular matrix is pivotal, such as cerebral cavernous malformations [ 33 , 34 , 35 ].…”

Section: Introductionmentioning

confidence: 99%

Rosiglitasone and ROCK Inhibitors Modulate Fibrogenetic Changes in TGF-β2 Treated Human Conjunctival Fibroblasts (HconF) in Different Manners

Oouchi

Watanabe

Ida

et al. 2021

IJMS

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Purpose: The effects of Rho-associated coiled-coil containing protein kinase (ROCK) 1 and 2 inhibitor, ripasudil hydrochloride hydrate (Rip), ROCK2 inhibitor, KD025 or rosiglitazone (Rosi) on two-dimension (2D) and three-dimension (3D) cultured human conjunctival fibroblasts (HconF) treated by transforming growth factor (TGFβ2) were studied. Methods: Two-dimension and three-dimension cultured HconF were examined by transendothelial electrical resistance (TEER, 2D), size and stiffness (3D), and the expression of the extracellular matrix (ECM) including collagen1 (COL1), COL4 and COL6, fibronectin (FN), and α-smooth muscle actin (αSMA) by quantitative PCR (2D, 3D) in the presence of Rip, KD025 or Rosi. Results: TGFβ2 caused a significant increase in (1) the TEER values (2D) which were greatly reduced by Rosi, (2) the stiffness of the 3D organoids which were substantially reduced by Rip or KD025, and (3) TGFβ2 induced a significant up-regulation of all ECMs, except for COL6 (2D) or αSMA (3D), and down-regulation of COL6 (2D). Rosi caused a significant up-regulation of COL1, 4 and 6 (3D), and down-regulation of COL6 (2D) and αSMA (3D). Most of these TGFβ2-induced expressions in the 2D and αSMA in the 3D were substantially inhibited by KD025, but COL4 and αSMA in 2D were further enhanced by Rip. Conclusion: The findings reported herein indicate that TGFβ2 induces an increase in fibrogenetic changes on the plane and in the spatial space, and are inhibited by Rosi and ROCK inhibitors, respectively.

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Section: Introductionmentioning

confidence: 99%

Rosiglitasone and ROCK Inhibitors Modulate Fibrogenetic Changes in TGF-β2 Treated Human Conjunctival Fibroblasts (HconF) in Different Manners

Oouchi

Watanabe

Ida

et al. 2021

IJMS

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“…The CSC interacts with other proteins and has affinity for a wide range of ligands; interactions with ligands contribute to cellular processes including cell migration, adhesion and apoptosis (Hilder et al., 2007; Zhang et al., 2001a, 2008, 2017). CCM proteins have been shown to alter pathways associated with angiogenesis, the process of new blood vessel development (Faurobert and Albiges-Rizo, 2010; He et al., 2010; Plummer et al., 2005; Scimone et al., 2015; Stockton et al., 2010), vascular angiogenesis (Zhang et al., 2005; Zhang et al., 2001a, b), blood vessel stability (Liu et al., 2010), cell adhesion to extracellular matrix, tube formation and endothelial cell morphogenesis (Faurobert and Albiges-Rizo, 2010; Liu et al., 2011). An association between vascular endothelial growth factor (VEGF) and CCM's have also been correlated to angiogenesis pathways, creating a more complex understanding of how all these pathways coordinate together (Distefano et al., 2014; He et al., 2010; Hoeben et al., 2004; Sun et al., 2003).…”

Section: Introductionmentioning

confidence: 99%

Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

Abou‐Fadel

Vasquez

Grajeda

et al. 2019

Heliyon

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A B S T R A C TCerebral cavernous malformations (CCMs) are characterized by abnormally dilated intracranial capillaries that result in increased susceptibility to stroke. Three genes have been identified as causes of CCMs; KRIT1 (CCM1), MGC4607 (CCM2) and PDCD10 (CCM3); one of them is disrupted in most CCM cases. It was demonstrated that both CCM1 and CCM3 bind to CCM2 to form a CCM signaling complex (CSC) to modulate angiogenesis. In this report, we deployed both RNA-seq and proteomic analysis of perturbed CSC after depletion of one of three CCM genes to generate interactomes for system-wide studies. Our results demonstrated a unique portrait detailing alterations in angiogenesis and vascular integrity. Interestingly, only in-direct overlapped alterations between RNA and protein levels were detected, supporting the existence of multiple layers of regulation in CSC cascades. Notably, this is the first report identifying that both β4 integrin and CAV1 signaling are downstream of CSC, conveying the angiogenic signaling. Our results provide a global view of signal transduction modulated by the CSC, identifies novel regulatory signaling networks and key cellular factors associated with CSC.Heliyon 5 (2019) e02899 Protein extraction for HBMVEC cells and zebrafish embryosHBMVEC cells and zebrafish embryos were lysed using a digital sonifier cell disruptor (Branson model 450 with model 102C converter and double step microtip) in ice cold lysis buffer containing 50 mM Tris-HCl (pH 7.5), 150 mM NaCl, 0.5% NP-40 (Sigma), 50 mM sodium fluoride (Sigma), 1 mM PMSF (Sigma), 1 mM dithiothreitol (Invitrogen) and EDTA-free complete protease inhibitor (Roche). The concentration of protein lysates were measure by Qubit assay (Invitrogen) before analysis.

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“…SWI sequence on 4/16/2018 showed more microhemorrhagic lesions and larger lesion size in the brain than SWI on 12/25/2017, which was the main reason for the progressively worsening headaches; 2) the patient with CCMs simultaneously suffered from multiple nodular skin lesions with a diameter of about 1 cm, which was rare in CCMs; 3) about 150 different mutations have been found in CCM1 leading to CCMs. 29 40 different mutations in CCM2 30 and 15 different mutations in CCM3 have been identified in Western countries. 31 It appears that CCM1 is the dominant genetic cause of CCMs in Chinese people.…”

Section: Discussionmentioning

confidence: 99%

<p>A novel PDCD10 gene mutation in cerebral cavernous malformations: a case report and review of the literature</p>

Yu¹,

Jin²,

You³

et al. 2019

JPR

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Cerebral cavernous malformations (CCMs) are one of the most common types of vascular malformation, which are featured enlarged and irregular small blood vessels. The cavernous cavities are merely composed of a single layer of endothelial cells and lack other support tissues, such as elastic fibers and smooth muscle, which make them elastic. CCMs may develop in sporadic or familial forms with autosomal dominant inheritance. Mutations have been identified in three genes: KRIT1, MGC4607, and PDCD10 . Here, we report a typical case of CCMs in a 44-year-old woman associated with a novel mutation in PDCD10 gene. The patient, diagnosed with CCMs, has been suffering from headache for several months. Analyses of the Whole Exome Sequencing revealed a novel disease-associated mutation in the already known disease-associated PDCD10 gene. This mutation consists a nucleotide deletion (c.212delG) within the exon 4, resulting in premature protein termination (p.S71Tfs*18). This novel mutation significantly enriches the spectrum of mutations responsible for CCMs, providing a new evidence for further clarifying the genotype–phenotype correlations in CCMs patients.

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Detection of Novel Mutation in Ccm3 Causes Familial Cerebral Cavernous Malformations

Cited by 28 publications

References 17 publications

Rosiglitasone and ROCK Inhibitors Modulate Fibrogenetic Changes in TGF-β2 Treated Human Conjunctival Fibroblasts (HconF) in Different Manners

Rosiglitasone and ROCK Inhibitors Modulate Fibrogenetic Changes in TGF-β2 Treated Human Conjunctival Fibroblasts (HconF) in Different Manners

Systems-wide analysis unravels the new roles of CCM signal complex (CSC)

<p>A novel PDCD10 gene mutation in cerebral cavernous malformations: a case report and review of the literature</p>

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