scholarly journals Abortive intussusceptive angiogenesis causes multi-cavernous vascular malformations

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Wenqing Li ◽  
Virginia Tran ◽  
Iftach Shaked ◽  
Belinda Xue ◽  
Thomas Moore ◽  
...  
Keyword(s):  
Blood Flow ◽  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Normal Process ◽  
Adult Fish ◽  
Venous Plexus ◽  
Cavernous Malformations ◽  
Over Expression ◽  
Intussusceptive Angiogenesis ◽  
Common Pathogenesis

Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to induce mosaic inactivation of zebrafish ccm2 resulting in a novel lethal multi-cavernous lesion in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic those that mediate intussusceptive angiogenesis; however, in contrast to the normal process, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resultant aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires the flow-regulated transcription factor KLF2; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe a zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.

scholarly journals Abortive Intussusceptive Angiogenesis Causes Multi-Cavernous Vascular Malformations

2020 ◽  
Author(s):  
Wenqing Li ◽  
Virginia Tran ◽  
Iftach Shaked ◽  
Belinda Xue ◽  
Thomas Moore ◽  
...  
Keyword(s):  
Developmental Biology ◽  
Blood Flow ◽  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Adult Fish ◽  
Venous Plexus ◽  
Cavernous Malformations ◽  
Over Expression ◽  
Intussusceptive Angiogenesis ◽  
Common Pathogenesis

Mosaic inactivation of CCM2 in humans causes cerebral cavernous malformations (CCMs) containing adjacent dilated blood-filled multi-cavernous lesions. We used CRISPR-Cas9 mutagenesis to inactivate zebrafish ccm2 resulting in novel lethal multi-cavernous lesions in the embryonic caudal venous plexus (CVP) caused by obstruction of blood flow by intraluminal pillars. These pillars mimic intussusceptive angiogenesis; however, the pillars failed to fuse to split the pre-existing vessel in two. Abortive intussusceptive angiogenesis stemmed from mosaic inactivation of ccm2 leading to patchy klf2a over-expression and resulting aberrant flow signaling. Surviving adult fish manifested histologically-typical hemorrhagic CCM. Formation of mammalian CCM requires flow-regulated transcription factors, KLF2 and KLF4; fish CCM and the embryonic CVP lesion failed to form in klf2a null fish indicating a common pathogenesis with the mammalian lesion. These studies describe the first zebrafish CCM model and establish a mechanism that can explain the formation of characteristic multi-cavernous lesions.Subject termsAnimal Models of Human Disease, Developmental Biology, Vascular Biology, Pathophysiology

scholarly journals Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Santhilal Subhash ◽  
Norman Kalmbach ◽  
Florian Wegner ◽  
Susanne Petri ◽  
Torsten Glomb ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Vascular Malformations ◽  
Cerebrovascular Disorders ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Low Flow ◽  
Pcr Analysis ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Non Coding Rnas

AbstractCerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.

Are cavernous sinus hemangiomas and cavernous malformations different entities?

2006 ◽  
Vol 21 (1) ◽  
pp. 1-5 ◽  
Author(s):  
L. Fernando Gonzalez ◽  
Gregory P. Lekovic ◽  
Jennifer Eschbacher ◽  
Stephen Coons ◽  
Randall W. Porter ◽  
...  
Keyword(s):  
Cavernous Sinus ◽  
Cavernous Malformation ◽  
Vascular Malformations ◽  
Response To Treatment ◽  
Vascular Tumors ◽  
Cerebral Cavernous Malformations ◽  
Imaging Studies ◽  
Cavernous Malformations ◽  
Cavernous Hemangiomas

✓Cavernous hemangiomas that occur within the cavernous sinus (CS) are different from cerebral cavernous malformations (CMs) clinically, on imaging studies, and in their response to treatment. Moreover, CMs are true vascular malformations, whereas hemangiomas are benign vascular tumors. Because of these differences, the authors suggest that these two entities be analyzed and grouped separately. Unfortunately, despite these differences, much confusion exists in the literature as to the nature, behavior, and classification of these two distinct lesions. This confusion is exacerbated by subtle histological differences and the inconsistent use of nomenclature. The authors use the term “cavernous malformation” to refer to intraaxial lesions only; they prefer to use the term “cavernous sinus hemangioma” to refer to extraaxial, intradural hemangiomas of the CS.

scholarly journals Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

2011 ◽  
Vol 208 (9) ◽  
pp. 1835-1847 ◽  
Author(s):  
Gwénola Boulday ◽  
Noemi Rudini ◽  
Luigi Maddaluno ◽  
Anne Blécon ◽  
Minh Arnould ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Vascular Lesions ◽  
Developmental Timing ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

scholarly journals A Novel CCM2 Missense Variant Caused Cerebral Cavernous Malformations in a Chinese Family

2021 ◽  
Vol 14 ◽  
Author(s):  
Guoqing Han ◽  
Li Ma ◽  
Huanhuan Qiao ◽  
Lin Han ◽  
Qiaoli Wu ◽  
...  
Keyword(s):  
Vascular Malformations ◽  
Case Reports ◽  
Chinese Family ◽  
Incomplete Penetrance ◽  
Cerebral Cavernous Malformations ◽  
Missense Mutations ◽  
Inherited Disease ◽  
Cavernous Malformations ◽  
Direct Dna Sequencing ◽  
Number Of Patients

Cerebral cavernous malformations (CCMs) are common vascular malformations in the central nervous system. Familial CCMs (FCCMs) are autosomal dominant inherited disease with incomplete penetrance and variable symptoms. Mutations in the KRIT1, CCM2, and PDCD10 genes cause the development of FCCM. Approximately 476 mutations of three CCM-related genes have been reported, most of which were case reports, and lack of data in stable inheritance. In addition, only a small number of causative missense mutations had been identified in patients. Here, we reported that 8/20 members of a Chinese family were diagnosed with CCMs. By direct DNA sequencing, we found a novel variant c.331G > C (p.A111P) in exon 4 of the CCM2 gene, which was a heterozygous exonic variant, in 7/20 family members. We consider this variant to be causative of disease due to a weaken the protein–protein interaction between KRIT1 and CCM2. In addition, we also found the exon 13 deletion in KRIT1 coexisting with the CCM2 mutation in patient IV-2, and this was inherited from her father (patient III-1H). This study of a Chinese family with a large number of patients with CCMs and stable inheritance of a CCM2 mutation contributes to better understanding the spectrum of gene mutations in CCMs.

scholarly journals Genetic Genealogy Uncovers a Founder Deletion Mutation in the Cerebral Cavernous Malformations 2 Gene

2021 ◽  
Author(s):  
Carol J Gallione ◽  
Matthew R Detter ◽  
Henrietta M Christmas ◽  
Cornelia Lee ◽  
Douglas A Marchuk
Keyword(s):  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Autosomal Dominant Trait ◽  
Cavernous Malformations ◽  
North American Continent ◽  
The North ◽  
Genealogical Data ◽  
The Brain ◽  
Recombination Junction ◽  
Pair Level

Abstract Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2-10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700’s. These haplotype and genealogical data suggest that these families and the remaining “unrelated” samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.

Cerebral Cavernous Malformations and Pregnancy

Neurosurgery ◽  
2012 ◽  
Vol 71 (3) ◽  
pp. 626-631 ◽  
Author(s):  
Christopher D. Witiw ◽  
Amal Abou-Hamden ◽  
Abhaya V. Kulkarni ◽  
Joseph A. Silvaggio ◽  
Carol Schneider ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Intracranial Hemorrhage ◽  
Health Care Professionals ◽  
Vascular Malformations ◽  
Post Partum ◽  
Study Group ◽  
Cerebral Cavernous Malformations ◽  
Pregnancy Risk ◽  
Cavernous Malformations ◽  
University Of Toronto

Abstract BACKGROUND: Cerebral cavernous malformations are brain vascular malformations associated with intracranial hemorrhage. It is unclear whether pregnancy is a risk factor for hemorrhage, yet there is speculation that it may be. OBJECTIVE: To compare the risk of clinically significant hemorrhage during pregnancy and nonpregnancy. METHODS: A total of 186 patients from the University of Toronto Vascular Malformations Study Group were enrolled. The obstetrical history of each patient was collected and matched to their neurological history from the records of the study group. All hemorrhagic events occurring during childbearing years were associated with either a defined pregnancy risk period or nonpregnancy period. Patients were also asked to recall advice that they received from health care professionals regarding risk of hemorrhage in pregnancy. RESULTS: Among our patient population there were 349 pregnancies (283 live births) and 49 hemorrhages during childbearing years, 3 of which were during pregnancy but none during delivery or within 6 weeks post partum. The hemorrhage rate for pregnant women was 1.15% (95% confidence interval: 0.23-3.35) per person-year and 1.01% (95% confidence interval: 0.75-1.36) per person-year for nonpregnant women. Relative risk of pregnancy was 1.13 (95% confidence interval: 0.34-3.75) (P = .84). Neurosurgeons and obstetricians were the source of most hemorrhage risk advice. The majority of neurosurgeons suggested that the risk was unchanged, but the obstetricians were divided. Four patients never conceived, and 2 others began contraception because of the advice that they received. CONCLUSION: The risk of intracranial hemorrhage from cerebral cavernous malformations is likely not changed during pregnancy, delivery, or post partum.

Cerebral cavernous malformations: epidemiological, clinical and diagnostic imaging aspects

2018 ◽  
Vol 8 (2) ◽  
pp. 8-17
Author(s):  
I. Czekalska ◽  
Z. Tyrakowska-Dadełło ◽  
P. Werel ◽  
E. Tarasów ◽  
E. Grodzka
Keyword(s):  
Clinical Symptoms ◽  
Vascular Malformations ◽  
Epileptic Seizures ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Large Size ◽  
Wide Range ◽  
Mean Size ◽  
The Central Nervous System

<b>Introduction:</b> Cerebral cavernous malformations (CCMs) are one of the most common vascular malformations of the central nervous system. Symptoms of CCMs are not typical; the disease can be asymptomatic or be manifested by a wide range of neurological symptoms. <b>Purpose:</b> To evaluate chosen epidemiologic and clinical issues as well as advanced imaging diagnostics of CCMs in computed tomography and magnetic resonance imaging. <b>Materials and methods:</b> The study was based on retrospective analysis of CT and MRI examinations from the 5 years period. The analysis covered 61 persons, 29 males, and 32 females. The CCMs were diagnosed based on MRI examination in 43 patients and CT in 13 patients. <b>Results:</b> The rate of CCMs occurrence in own material was 0.2%. Single lesions were present in 90.2%, while multiple in 9.8% of cases. Supratentorial CCMs were observed in 77% of cases whereas subtentorial in 23%. Mean size of CCMs in the supra- and subtentorial area equaled 10.6±6.3 and 15.1±5.8 mm, respectively (p<0.05). Clinical symptoms occurred in 65.8% of patients, most frequently in patients with CCMs above 5 mm or with subtentorial lesions. All CCMs were hyperdense in CT images, with calcifications in 13.1%. In MRI, malformations showed diverse intensity of the central part with peripheral low-intensity rim of hemosiderine deposits in T2-weighted images. <b>Conclusions:</b> The clinical symptoms occur in most cases of CCMs. These patients require periodic follow-up MRI examinations, specifically those with haemorrhagic incidents or epileptic seizures, with large size or subtentorial CCMs.

Novel CCM2 missense variants abrogating the CCM1–CCM2 interaction cause cerebral cavernous malformations

2020 ◽  
Vol 57 (6) ◽  
pp. 400-404
Author(s):  
Françoise Bergametti ◽  
Geraldine Viot ◽  
Christophe Verny ◽  
Marie Pierre Brechard ◽  
Christian Denier ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Complex Stability ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Cavernous Malformations ◽  
Missense Variants ◽  
The Central Nervous System ◽  
Ptb Domain

BackgroundCerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three CCM genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few CCM2 missense variants have been shown to be deleterious by modifying the ternary CCM complex stability.ObjectivesTo investigate the causality of novel missense CCM2 variants detected in patients with CCM.MethodsThe three CCM genes were screened in 984 patients referred for CCM molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the CCM2 missense variants located in the phosphotyrosine binding (PTB) domain.Results11 distinct CCM2 rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a loss of interaction between CCM1 and CCM2 was observed for all six variants.ConclusionWe showed, using co-immunoprecipitation experiments, that CCM2 missense variants located in the PTB domain were actually damaging by preventing the normal interaction between CCM1 and CCM2. These data are important for diagnosis and genetic counselling, which are challenging in patients harbouring such variants.

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