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1.
Ideggyogy Sz ; 72(7-8): 273-277, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31517460

RESUMO

Cerebral cavernous malformations (CCMs) represent a relatively rare and heterogeneous clinical entity with mutations identified in three genes. Both sporadic and familial forms have been reported. We present a young female patient with episodic paresthesia and headaches, but without acute neurological deficits. Her mother had a hemorrhaged cavernoma surgically removed 21 years ago. Cranial magnetic resonance imaging revealed multiple cavernous malformations in the size of a few millimeters and the ophthalmologic exam detected retinal blood vessel tortuosity in the proband. Targeted exome sequencing analysis identified a nonsense mutation in exon 16 of the KRIT1 gene, which resulted in a premature stop codon and a truncated protein underlying the abnormal development of cerebral and retinal blood vessels. This mutation with pathogenic significance has been reported before. Our case points to the importance of a thorough clinical and molecular work up despite the uncertain neurological complaints, since life style recommendations, imaging monitoring and genetic counseling may have major significance in the long term health of the patient.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Proteína KRIT1/genética , Vasos Retinianos/diagnóstico por imagem , Feminino , Cefaleia/etiologia , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Imagem por Ressonância Magnética , Mutação , Parestesia/etiologia , Linhagem , Deleção de Sequência/genética
2.
Nat Commun ; 10(1): 2817, 2019 06 27.
Artigo em Inglês | MEDLINE | ID: mdl-31249304

RESUMO

Sufficient vascular supply is indispensable for brain development and function, whereas dysfunctional blood vessels are associated with human diseases such as vascular malformations, stroke or neurodegeneration. Pericytes are capillary-associated mesenchymal cells that limit vascular permeability and protect the brain by preserving blood-brain barrier integrity. Loss of pericytes has been linked to neurodegenerative changes in genetically modified mice. Here, we report that postnatal inactivation of the Rbpj gene, encoding the transcription factor RBPJ, leads to alteration of cell identity markers in brain pericytes, increases local TGFß signalling, and triggers profound changes in endothelial behaviour. These changes, which are not mimicked by pericyte ablation, imperil vascular stability and induce the acquisition of pathological landmarks associated with cerebral cavernous malformations. In adult mice, loss of Rbpj results in bigger stroke lesions upon ischemic insult. We propose that brain pericytes can acquire deleterious properties that actively enhance vascular lesion formation and promote pathogenic processes.


Assuntos
Encéfalo/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/deficiência , Pericitos/metabolismo , Animais , Barreira Hematoencefálica/metabolismo , Encéfalo/citologia , Progressão da Doença , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Masculino , Camundongos Knockout
3.
Nat Commun ; 10(1): 2761, 2019 06 24.
Artigo em Inglês | MEDLINE | ID: mdl-31235698

RESUMO

Cerebral cavernous malformation (CCM) is a neurovascular familial or sporadic disease that is characterised by capillary-venous cavernomas, and is due to loss-of-function mutations to any one of three CCM genes. Familial CCM follows a two-hit mechanism similar to that of tumour suppressor genes, while in sporadic cavernomas only a small fraction of endothelial cells shows mutated CCM genes. We reported that in mouse models and in human patients, endothelial cells lining the lesions have different features from the surrounding endothelium, as they express mesenchymal/stem-cell markers. Here we show that cavernomas originate from clonal expansion of few Ccm3-null endothelial cells that express mesenchymal/stem-cell markers. These cells then attract surrounding wild-type endothelial cells, inducing them to express mesenchymal/stem-cell markers and to contribute to cavernoma growth. These characteristics of Ccm3-null cells are reminiscent of the tumour-initiating cells that are responsible for tumour growth. Our data support the concept that CCM has benign tumour characteristics.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Neoplasias do Sistema Nervoso Central/patologia , Células Endoteliais/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores/metabolismo , Encéfalo/irrigação sanguínea , Encéfalo/citologia , Encéfalo/patologia , Diferenciação Celular/genética , Linhagem Celular , Neoplasias do Sistema Nervoso Central/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Endotélio Vascular/citologia , Endotélio Vascular/patologia , Feminino , Técnicas de Inativação de Genes , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Mutação com Perda de Função , Proteínas de Membrana/metabolismo , Células-Tronco Mesenquimais/metabolismo , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/metabolismo
4.
Nat Commun ; 10(1): 1791, 2019 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-30996251

RESUMO

Apoptotic death of cells damaged by genotoxic stress requires regulatory input from surrounding tissues. The C. elegans scaffold protein KRI-1, ortholog of mammalian KRIT1/CCM1, permits DNA damage-induced apoptosis of cells in the germline by an unknown cell non-autonomous mechanism. We reveal that KRI-1 exists in a complex with CCM-2 in the intestine to negatively regulate the ERK-5/MAPK pathway. This allows the KLF-3 transcription factor to facilitate expression of the SLC39 zinc transporter gene zipt-2.3, which functions to sequester zinc in the intestine. Ablation of KRI-1 results in reduced zinc sequestration in the intestine, inhibition of IR-induced MPK-1/ERK1 activation, and apoptosis in the germline. Zinc localization is also perturbed in the vasculature of krit1-/- zebrafish, and SLC39 zinc transporters are mis-expressed in Cerebral Cavernous Malformations (CCM) patient tissues. This study provides new insights into the regulation of apoptosis by cross-tissue communication, and suggests a link between zinc localization and CCM disease.


Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Apoptose/fisiologia , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Transporte de Cátions/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Zinco/metabolismo , Animais , Animais Geneticamente Modificados , Apoptose/efeitos da radiação , Proteínas Reguladoras de Apoptose/genética , Encéfalo/patologia , Encéfalo/cirurgia , Caenorhabditis elegans/fisiologia , Caenorhabditis elegans/efeitos da radiação , Proteínas de Caenorhabditis elegans/genética , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Proteína KRIT1/genética , Proteína KRIT1/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Sistema de Sinalização das MAP Quinases/fisiologia , Camundongos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 7 Ativada por Mitógeno/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Mutagênese , Mutação , Fosforilação/fisiologia , Alinhamento de Sequência , Peixe-Zebra , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
5.
J Mol Neurosci ; 67(3): 467-471, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30701383

RESUMO

Cerebral cavernous malformation (CCM) is a congenital vascular anomaly that predominantly involves the central nervous system (CNS). CCM occurs in either a sporadic or an inherited form; the latter is called familial cerebral cavernous malformation (FCCM). FCCM has an autosomal dominant transmission with incomplete penetrance and variable clinical expression that is associated with germline mutations in the CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes. Herein, we disclose two novel heterozygous mutations in the CCM2 gene in a Chinese family: a deletion mutation (c.55C>T; p. R19X, 426) in exon 2 and a mutation (c.*18G>A) in the noncoding region of exon 10. Our findings provide new CCM2 gene mutation profiles and further evidence for phenotypic heterogeneity.


Assuntos
Proteínas de Transporte/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Mutação , Adulto , Idoso , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo
6.
Zhonghua Yu Fang Yi Xue Za Zhi ; 52(5): 545-551, 2018 May 06.
Artigo em Chinês | MEDLINE | ID: mdl-29747348

RESUMO

Objective: To investigate the effects of cerebral cavernous malformation 3 (CCM3) gene knockout on the lead exposure-induced blood-brain barrier malfunction in mice brain, and the relationship between CCM3 knockout and the Alzheimer's disease (AD). Methods: Wide type (WT) mice and CCM3(+)/- mice were divided into 4 groups, control group and lead exposed group in WT as well as CCM3(+/-) mice. Lead exposed groups were treated with 0.05% lead acetate in drinking water for 12 weeks, while control group drink deionized water freely. Blood lead and brain lead levels in each group were detected by graphite furnace atomic absorption spectrometry. The brain tissue of each group was made into paraffin sections, whose morphology were observed by HE staining. The expression of Aß(1-42) in brain tissue was detected by immunohistochemistry and the brain capillaries were labeled by VRGFR2. The protein expression of Claudin-5, ZO-1, and p-Tau was detected by Western blot. The brain tissue RNA was extracted and the relative expression of LRP-1 mRNA was detected by qRT-PCR. Results: The levels of blood lead WT (216.07±84.16) and CCM3(+/-) (189.64±101.86) µg/L in lead exposed group were higher than those in control group WT (19.52±11.46) and CCM3(+/-) (11.79±8.20) µg/L, the difference was statistically significant (t=4.18, P=0.006; t=3.79, P=0.016). The levels of brain lead WT (1.78±0.69) and CCM3(+/-) (1.74±0.66) µg/L were higher than those in control group WT (1.06±0.87) and CCM3(+/-) (0.97±0.64) µg/L, the difference was statistically significant (t=3.67, P=0.018; t=3.88, P=0.015). The HE staining showed no obvious lesions in the brain of each group of mice. The results of immunohistochemistry showed that there was no Aß(1)-42 deposition in the brain of mice in each group. The numbers of microvessels in the brain of CCM3(+/-) mice in the lead exposed group were decreased. Compared with the relative expression levels of Claudin-5 (WT: 1.30±0.03, CCM3(+/-): 1.07±0.08) in control group mice brain, the relative expression of Claudin-5 (WT: 0.96±0.04, CCM3(+/-): 0.59±0.01) was decreased with statistical significance (F=199.27, P<0.001). The relative expression level of LRP-1 gene mRNA in brain of lead exposed group (WT: 0.32±0.10, CCM3(+/-): 0.06±0.01) was higher than that of unexposed group (WT:1.00±0.06, CCM3(+/-):2.12±0.18), the difference was statistically significant (F=288.29, P<0.001). The relative expression level of LRP-1 gene mRNA in brain of CCM3(+)/- mice exposed to lead was lower than that of WT mice ((0.06±0.01)vs(0.32±0.10), t=26.90, P<0.001). Conclusion: The mice did not show significant AD-like lesions under low-does lead exposure, but resulted in early damage of brain blood-brain barrier and early changes of AD-like lesions in mice, with CCM3(+/-) mice being sensitive to lead exposure stronger than that of WT mice, suggesting that deletion of CCM3 gene may be one of the potential risk factors for accelerating the development of AD in mice exposed to lead.


Assuntos
Doença de Alzheimer/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Compostos Organometálicos/toxicidade , Animais , Western Blotting , Hemangioma Cavernoso do Sistema Nervoso Central/induzido quimicamente , Chumbo , Camundongos , RNA Mensageiro
8.
World Neurosurg ; 113: e247-e270, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29454117

RESUMO

OBJECTIVES: To understand the development of sporadic cerebral cavernous malformations (SCCM) comprehensively, we analyzed gene expression profiles in SCCMs by gene microarray. METHODS: The total number of the specimens collected in our study was 14, 7 of which were SCCMs, and the others were controls that were obtained from normal brain vessels. The total RNA was extracted and hybridized with oligonucleotide array containing 21522 genes. The analysis of Gene Ontology (GO) items and molecular pathways was performed based on the GO and Kyoto Encyclopedia of Genes and Genomes databases. The gene coexpression networks were constructed to identify the core genes regulating the progression of SCCMs. RESULTS: A total of 785 probes, showing differentially expressed genes (DEGs) between the 2 groups, were found by the gene chips. According to the analysis based on GO and Kyoto Encyclopedia of Genes and Genomes, 286 GO terms and 53 pathways were identified to be significantly relevant with the DEGs. All differential gene interactions were analyzed and the core genes were selected in the coexpression networks. CONCLUSIONS: The gene expression profiles obtained from SCCMs were significantly distinct from those of control brain vascular specimens. These DEGs are related to multiple molecular signal pathways, such as the mitogen-activated protein kinase pathway, cytokine-cytokine receptor interaction, focal adhesion, and inflammatory response. According to the analysis of the core genes selected in the gene coexpression networks, we postulated that CSF1R, XCL1, KCNMB1, RHOG, and TJP1 might exert enormous functions in the pathogenesis of SCCMs. However, further studies are required to aid in the clinical diagnosis and prevention of SCCMs.


Assuntos
Neoplasias Encefálicas/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteínas de Neoplasias/genética , Adolescente , Adulto , DNA Complementar/genética , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Ontologia Genética , Redes Reguladoras de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Neoplásico/genética , Reação em Cadeia da Polimerase em Tempo Real , Adulto Jovem
9.
Seizure ; 53: 72-74, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29145060

RESUMO

Cerebral cavernous malformations (CCMs) are vascular malformations which may occur in familial forms which have autosomal dominant inheritance. Mutations have been identified in three genes: KRIT1, MGC4607 and PDCD10. We have documented a novel mutation on KRIT1 gene, and the second to be reported in a Portuguese family. This mutation consists in a two nucleotide insertion (c.947_948insAC) within the exon 10, resulting in premature protein termination (p.Leu317Argfs*2). These findings will hopefully contribute to a better clinical, imaging and genetic characterisation of this disease, particularly while trying to identify the factors that influence its treatment and prognosis.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central , Proteína KRIT1/genética , Adulto , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/fisiopatologia , Humanos , Pessoa de Meia-Idade , Linhagem , Portugal
10.
J Exp Med ; 214(11): 3331-3346, 2017 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-28970240

RESUMO

KRIT1 mutations are the most common cause of cerebral cavernous malformation (CCM). Acute Krit1 gene inactivation in mouse brain microvascular endothelial cells (BMECs) changes expression of multiple genes involved in vascular development. These changes include suppression of Thbs1, which encodes thrombospondin1 (TSP1) and has been ascribed to KLF2- and KLF4-mediated repression of Thbs1 In vitro reconstitution of TSP1 with either full-length TSP1 or 3TSR, an anti-angiogenic TSP1 fragment, suppresses heightened vascular endothelial growth factor signaling and preserves BMEC tight junctions. Furthermore, administration of 3TSR prevents the development of lesions in a mouse model of CCM1 (Krit1ECKO ) as judged by histology and quantitative micro-computed tomography. Conversely, reduced TSP1 expression contributes to the pathogenesis of CCM, because inactivation of one or two copies of Thbs1 exacerbated CCM formation. Thus, loss of Krit1 function disables an angiogenic checkpoint to enable CCM formation. These results suggest that 3TSR, or other angiogenesis inhibitors, can be repurposed for TSP1 replacement therapy for CCMs.


Assuntos
Terapia Genética/métodos , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/terapia , Proteína KRIT1/metabolismo , Trombospondina 1/metabolismo , Animais , Células Cultivadas , Células Endoteliais/metabolismo , Perfilação da Expressão Gênica/métodos , Células HEK293 , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Proteína KRIT1/genética , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Interferência de RNA , Trombospondina 1/genética
11.
Circ Res ; 121(8): 981-999, 2017 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-28963191

RESUMO

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-ß/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-ß/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-ß/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-ß/BMP receptor complex and the second to increased signaling sensitivity to TGF-ß/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability.


Assuntos
Vasos Sanguíneos/metabolismo , Proteínas Morfogenéticas Ósseas/metabolismo , Neovascularização Fisiológica , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Malformações Vasculares/metabolismo , Animais , Vasos Sanguíneos/anormalidades , Vasos Sanguíneos/fisiopatologia , Proteínas Morfogenéticas Ósseas/genética , Modelos Animais de Doenças , Predisposição Genética para Doença , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/fisiopatologia , Humanos , Camundongos Transgênicos , Mutação , Fenótipo , Fatores de Risco , Telangiectasia Hemorrágica Hereditária/genética , Telangiectasia Hemorrágica Hereditária/metabolismo , Telangiectasia Hemorrágica Hereditária/fisiopatologia , Fator de Crescimento Transformador beta/genética , Malformações Vasculares/genética , Malformações Vasculares/fisiopatologia
12.
Curr Cardiol Rep ; 19(12): 122, 2017 10 18.
Artigo em Inglês | MEDLINE | ID: mdl-29046973

RESUMO

PURPOSE OF REVIEW: This study aims to review the current epidemiology and clinical management of patients with cavernous malformations (CM). RECENT FINDINGS: Hemorrhage is the most feared complication and leads to morbidity in patients with CM. Multiple studies including three meta-analyses have provided useful estimates of hemorrhage risk, but have failed to identify a modifiable risk factor for prevention of cavernous malformation related hemorrhage. In treating the CM itself, surgical risk is weighed against the natural history. However, accumulating knowledge regarding the roles of CCM 1, 2, and 3 genes has led to the discovery of potential therapeutic targets. The risk of future hemorrhage in patients with CM is highest in those who have had previously clinical hemorrhages. Estimated risks are helpful in counseling patients and comparing to the risk of surgery. Future clinical trials of candidate medications are likely to target those patients with prior clinical hemorrhage in whom the surgical risk is deemed high.


Assuntos
Anticonvulsivantes/uso terapêutico , Hemorragia Cerebral/prevenção & controle , Hemangioma Cavernoso do Sistema Nervoso Central/terapia , Procedimentos Neurocirúrgicos , Radiocirurgia , Convulsões/prevenção & controle , Proteínas Reguladoras de Apoptose/genética , Proteínas de Transporte/genética , Hemorragia Cerebral/etiologia , Gerenciamento Clínico , Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Proteína KRIT1/genética , Terapia a Laser , Imagem por Ressonância Magnética , Proteínas de Membrana/genética , Terapia de Alvo Molecular , Proteínas Proto-Oncogênicas/genética , Convulsões/tratamento farmacológico , Convulsões/etiologia , Técnicas Estereotáxicas , Tomografia Computadorizada por Raios X
13.
J Neurol Sci ; 380: 31-37, 2017 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-28870584

RESUMO

Cerebral cavernous malformations (CCMs) are clusters of capillaries in the brain that may cause focal deficits or seizures in affected patients. They occur in both sporadic and inherited autosomal dominant form. Germline mutations in CCM1, CCM2 and CCM3 were identified in familial cases. Over the past 13years we performed sequencing and MLPA of the CCM genes in all sporadic and familial CCM cases coming from some hospital clinics of Neurology and Neurosurgery of Messina and other Italian cities. Our results showed that CCM sporadic patients, negative for previously reported CCM gene causative mutations, always carried known CCM polymorphisms. Previously, we reported polymorphisms in CCM2 gene associated with an increase in risk for CCM. Here, we undertook a case-control study to investigate the possible association of others polymorphisms (c.485+65 C/G, c.989+63 C/G, c.1980 A/G in CCM1 gene, c.472+127 C/T in CCM2 and c.150 G/A in CCM3) with CCMs. The five polymorphisms were characterized in 64 sporadic patients and in 90 healthy controls by ASO-PCR. Statistically significant differences in frequencies between patients and controls were found for c.485+65C/G, c.1980 A/G and c.472+127C/T polymorphisms. For c.485+65C/G polymorphism, a higher frequency of mutated allele (G) was found in patients group (9%) than in controls (2%) (p=0.0041); for c.1980 A/G polymorphism, we found a frequency of mutated allele (G) higher in the control group (25%) compared to that of patients (8%) (p=0.0396). Same trend was observed for c.472+127C/T polymorphism (T allele frequency=34% and 6% in control group and patients, respectively; p=0.0001). Polymorphisms c.485+65C/G, c.1980 A/G and c.472+127C/T were associated with an increased risk of CCM as indicated by odds ratio values. Furthermore, c.1980 A/G and c.472+127C/T polymorphisms were associated with less severe CCM symptomatology. Identification of these polymorphisms in CCM sporadic patient may represent a useful tool for clinicians to determine prognosis, scheduled periodic checks and appropriate treatment strategy.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Transporte/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteína KRIT1/genética , Proteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Criança , Estudos de Coortes , Gerenciamento Clínico , Feminino , Frequência do Gene , Predisposição Genética para Doença , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Adulto Jovem
14.
J AAPOS ; 21(5): 426-429.e1, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28867399

RESUMO

Evaluation for intracranial lesions in a patient with retinal cavernous hemangiomas is vital for early recognition of this heritable and potentially life-threatening disease. We report a case of a highly penetrant but variably expressed form of cerebral cavernous malformation syndrome with cerebral, cutaneous, and retinal cavernomas in a family found to harbor a nonsense mutation of the CCM1 gene.


Assuntos
Códon sem Sentido , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso/genética , Proteína KRIT1/genética , Síndromes Neurocutâneas/genética , Neoplasias da Retina/genética , Neoplasias Cutâneas/genética , Criança , Análise Mutacional de DNA , Feminino , Angiofluoresceinografia , Hemangioma Cavernoso/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Humanos , Síndromes Neurocutâneas/patologia , Linhagem , Neoplasias da Retina/patologia , Neoplasias Cutâneas/patologia , Tomografia de Coerência Óptica
17.
Artigo em Russo | MEDLINE | ID: mdl-28745674

RESUMO

AIM: To identify mutations in cerebral cavernous malformation (CCM) genes in patients with hereditary and sporadic CCMs in the Russian population. MATERIAL AND METHODS: Blood samples from 73 randomly selected patients, including 29 MRI-confirmed familial cases, 8 clinically confirmed familial cases and 38 so-called sporadic cases, were examined. A search for large deletions/duplications was performed using multiplex ligation-dependent probe amplification (MPLA). For MLPA-negative samples, the whole genome sequencing was performed to search for single nucleotide polymorphisms (SNP). RESULTS: Deletions in three genes (ССМ1, ССМ2, ССМ3) were identified in 14 patients, including 5 without definitely established familial type, in whom the familial character of disease was not confirmed by clinical and neuroimaging results. SNP mutations were found in 13 patients, CCM gene mutations in 27. Mutations were detected in 91.7% of familial cases. In two patients, new CCM3 deletions were identified. Gene distribution was as follows: 60.7 for CCM1, 32.2 for CCM2 and 7.1% for CCM3. In two members of a family with hereditary CCMs, no high effect mutations in the known CCM genes were found. Patients with mutations had greater severity of disease. Two patients with CCM3 mutations demonstrated the most aggressive clinical course. De novo formation and growth of CCM were observed only in patients with mutations. CONCLUSION: The distribution of pathogenic mutations in known CCM genes is consistent with other large-scale studies. Familial CCMs are associated with more severe disease course and may be caused by mutations beyond the known CCM genes.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Encéfalo/anormalidades , Proteínas de Transporte/genética , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteína KRIT1/genética , Proteínas de Membrana/genética , Proteínas Proto-Oncogênicas/genética , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Análise Mutacional de DNA , Feminino , Humanos , Masculino , Reação em Cadeia da Polimerase Multiplex , Mutação , Polimorfismo de Nucleotídeo Único , Federação Russa , Adulto Jovem
18.
World Neurosurg ; 105: 1034.e1-1034.e6, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28602929

RESUMO

We report on a patient with 2 Mendelian diseases-symptomatic multiple familial cerebral cavernous malformations (FCCMs) and Wilson disease. Genetic analysis revealed single nucleotide polymorphisms in genes CCM2 and CCM3, associated with cavernous malformations, and homozygote mutation in the ATP7B gene, responsible for Wilson disease. FCCMs were symptomatic in 3 generations. The patient also had multiple lipomatosis, which is suggested to be a familial syndrome. In recent years there has been an increasing amount of publications linking FCCMs with other pathology, predominantly with extracranial and intracranial mesenchymal anomalies. The present study is the description of an unusual association between 2 independent hereditary diseases of confirmed genetic origin-a combination that has not been described previously.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/complicações , Degeneração Hepatolenticular/complicações , Lipoma/complicações , Proteínas Reguladoras de Apoptose/genética , Encéfalo/diagnóstico por imagem , Proteínas de Transporte/genética , Saúde da Família , Feminino , Seguimentos , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico por imagem , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/cirurgia , Degeneração Hepatolenticular/diagnóstico por imagem , Degeneração Hepatolenticular/cirurgia , Humanos , Lipoma/diagnóstico por imagem , Lipoma/genética , Lipoma/cirurgia , Imagem por Ressonância Magnética , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Mutação/genética , Proteínas Proto-Oncogênicas/genética , Ventriculostomia/métodos
19.
Eur J Med Genet ; 60(9): 479-484, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28645800

RESUMO

Cerebral cavernous malformations (CCM) are vascular lesions of the central nervous system that can cause headaches, seizures and hemorrhagic stroke. Disease-associated mutations have been identified in three genes: CCM1/KRIT1, CCM2 and CCM3/PDCD10. The precise proportion of deep-intronic variants in these genes and their clinical relevance is yet unknown. Here, a long-range PCR (LR-PCR) approach for target enrichment of the entire genomic regions of the three genes was combined with next generation sequencing (NGS) to screen for coding and non-coding variants. NGS detected all six CCM1/KRIT1, two CCM2 and four CCM3/PDCD10 mutations that had previously been identified by Sanger sequencing. Two of the pathogenic variants presented here are novel. Additionally, 20 stringently selected CCM index cases that had remained mutation-negative after conventional sequencing and exclusion of copy number variations were screened for deep-intronic mutations. The combination of bioinformatics filtering and transcript analyses did not reveal any deep-intronic splice mutations in these cases. Our results demonstrate that target enrichment by LR-PCR combined with NGS can be used for a comprehensive analysis of the entire genomic regions of the CCM genes in a research context. However, its clinical utility is limited as deep-intronic splice mutations in CCM1/KRIT1, CCM2 and CCM3/PDCD10 seem to be rather rare.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Proteínas de Transporte/genética , Testes Genéticos/métodos , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Proteína KRIT1/genética , Proteínas de Membrana/genética , Mutação , Proteínas Proto-Oncogênicas/genética , Processamento de RNA , Adolescente , Adulto , Criança , Variações do Número de Cópias de DNA , Feminino , Hemangioma Cavernoso do Sistema Nervoso Central/diagnóstico , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Íntrons , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA/métodos
20.
Handb Clin Neurol ; 143: 267-277, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28552149

RESUMO

Cavernous malformations (CMs) are low-pressure angiographically occult lesions, composed of blood-filled sinusoidal locules known as "caverns." Although these lesions were once believed to be congenital in nature, there is compelling evidence to support de novo formation of CMs as well. They can occur as sporadic lesions or be inherited in an autosomal-dominant phenotype in familial forms of the disease. The pathophysiology of CMs is commonly believed to be due to abnormal vascular pathology. Three genes, CCM1, CCM2, and CCM3, have been extensively studied for their role in vascular pathology, resulting in abnormal angiogenesis and compromising the structural integrity of vessel endothelial cell. The expression of growth factors has been researched to gain insight into the dynamic behavior of CM lesions. Gross and microscopic images are utilized in this chapter to illustrate the pathologic findings of these lesions. Ultrastructural analysis demonstrates the aberrations in CM endothelial cells and structural integrity that may provide better understanding into how and why these lesions have a propensity to hemorrhage.


Assuntos
Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Malformações Arteriovenosas Intracranianas/patologia , Proteínas Reguladoras de Apoptose/genética , Proteínas de Transporte/genética , Células Endoteliais/patologia , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Humanos , Malformações Arteriovenosas Intracranianas/genética , Proteína KRIT1/genética , Proteínas de Membrana/genética , Microscopia Eletrônica de Varredura , Fenótipo , Proteínas Proto-Oncogênicas/genética
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