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1.
Hum Genomics ; 17(1): 24, 2023 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-36941667

RESUMO

BACKGROUND: Moyamoya angiopathy (MMA) is a rare cerebrovascular condition leading to stroke. Mutations in 15 genes have been identified in Mendelian forms of MMA, but they explain only a very small proportion of cases. Our aim was to investigate the genetic basis of MMA in consanguineous patients having unaffected parents in order to identify genes involved in autosomal recessive MMA. METHODS: Exome sequencing (ES) was performed in 6 consecutive consanguineous probands having MMA of unknown etiology. Functional consequences of variants were assessed using western blot and protein 3D structure analyses. RESULTS: Causative homozygous variants of NOS3, the gene encoding the endothelial nitric oxide synthase (eNOS), and GUCY1A3, the gene encoding the alpha1 subunit of the soluble guanylate cyclase (sGC) which is the major nitric oxide (NO) receptor in the vascular wall, were identified in 3 of the 6 probands. One NOS3 variant (c.1502 + 1G > C) involves a splice donor site causing a premature termination codon and leads to a total lack of eNOS in endothelial progenitor cells of the affected proband. The other NOS3 variant (c.1942 T > C) is a missense variant located into the flavodoxine reductase domain; it is predicted to be destabilizing and shown to be associated with a reduction of eNOS expression. The GUCY1A3 missense variant (c.1778G > A), located in the catalytic domain of the sGC, is predicted to disrupt the tridimensional structure of this domain and to lead to a loss of function of the enzyme. Both NOS3 mutated probands suffered from an infant-onset and severe MMA associated with posterior cerebral artery steno-occlusive lesions. The GUCY1A3 mutated proband presented an adult-onset MMA associated with an early-onset arterial hypertension and a stenosis of the superior mesenteric artery. None of the 3 probands had achalasia. CONCLUSIONS: We show for the first time that biallelic loss of function variants in NOS3 is responsible for MMA and that mutations in NOS3 and GUCY1A3 are causing fifty per cent of MMA in consanguineous patients. These data pinpoint the essential role of the NO pathway in MMA pathophysiology.


Assuntos
Doença de Moyamoya , Óxido Nítrico Sintase Tipo III , Óxido Nítrico , Guanilil Ciclase Solúvel , Adulto , Humanos , Doença de Moyamoya/genética , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/genética , Transdução de Sinais/genética , Guanilil Ciclase Solúvel/genética
2.
Stroke ; 51(4): 1272-1278, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31992178

RESUMO

Background and Purpose- Cerebral cavernous malformations (CCMs) are vascular malformations of the brain that lead to cerebral hemorrhages. A pharmacological treatment is needed especially for patients with nonoperable deep-seated lesions. We and others obtained CCM mouse models that were useful for mechanistic studies and rapid trials testing the preventive effects of candidate drugs. The shortened lifespan of acute mouse models hampered evaluation of compounds that would not only prevent lesion appearance but also cure preexisting lesions. Indirubin-3'-monoxime previously demonstrated its efficacy to reverse the cardiac phenotype of ccm2m201 zebrafish mutants and to prevent lesion development in an acute CCM2 mouse model. In the present article, we developed and characterized a novel chronic CCM2 mouse model and evaluated the curative therapeutic effect of indirubin-3'-monoxime after CCM lesion development. Methods- The chronic mouse model was obtained by a postnatal induction of brain-endothelial-cell-specific ablation of the Ccm2 gene using the inducible Slco1c1-CreERT2 mouse line. Results- We obtained a fully penetrant novel CCM chronic mouse model without any obvious off-target phenotypes and compatible with long-term survival. By 3 months of age, CCM lesions ranging in size from small isolated lesions to multiple caverns developed throughout the brain. Lesion burden was quantified in animals from 1 week to 5 months of age. Clear signs of intracerebral hemorrhages were noticed in brain-endothelial-cell-specific ablation of the Ccm2 gene. In contrast with its preventive effect in the acute CCM2 mouse model, a 20 mg/kg indirubin-3'-monoxime treatment for 3 weeks in 3-month old animals neither had any beneficial effect on the lesion burden nor alleviated cerebral hemorrhages. Conclusions- The brain-endothelial-cell-specific ablation of the Ccm2 gene chronic model is a strongly improved disease model for the CCM community whose challenge today is to decipher which candidate drugs might have a curative effect on patients' preexisting lesions. Visual Overview- An online visual overview is available for this article.


Assuntos
Encéfalo/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia , Modelos Animais de Doenças , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/patologia , Proteínas dos Microfilamentos/genética , Animais , Neoplasias do Sistema Nervoso Central/metabolismo , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas dos Microfilamentos/deficiência
3.
Stroke ; 50(4): 789-796, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30908154

RESUMO

Background and Purpose Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy outside of Asia. In Japanese patients, a vast majority of patients carry the founder p.R4810K variant in the RNF213 gene, and familial cases are around 10%. In European patients, data about familial occurrence are limited. The aim of this study was to characterize the clinical and molecular features of several European families with a parent-to-child transmission of MMA. Methods Out of 126 MMA probands referred, we identified 113 sporadic probands and 13 familial probands. Segregation analysis showed a vertical parent-to-child pattern of inheritance in the families of 5 of these probands. All 5 families were of German or Dutch ancestry. We investigated the clinical features of affected members and used whole-exome sequencing to screen RNF213 and 13 genes involved in Mendelian MMA and to identify genes recurrently mutated in these families. Results Twelve affected MMA patients were identified, including 9 females and 3 males. Age at clinical onset ranged from 11 to 65 years. In 3 of 5 families, associated livedo racemosa was found. We did not detect any deleterious variants in the 13 known MMA genes. RNF213 rare missense variants predicted to be pathogenic were detected in all affected members of 2 of these families, as well as 2 candidate variants of the PALD1 gene. Conclusions Nonsyndromic MMA was identified in 5 European families, including 2 to 3 clinically affected cases segregating with a parent-to-child pattern of inheritance in each family. Molecular screening detected rare deleterious variants within RNF213 and PALD1 in all affected members of 2 of these 5 families, as well as in some clinically unaffected members. Altogether these data raise the difficult and, to date unanswered, question of the medical indication of presymptomatic screening.


Assuntos
Adenosina Trifosfatases/genética , Predisposição Genética para Doença , Doença de Moyamoya/diagnóstico , Mutação , Ubiquitina-Proteína Ligases/genética , Adolescente , Adulto , Idade de Início , Idoso , Alelos , Criança , Europa (Continente) , Feminino , Frequência do Gene , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Moyamoya/genética , Linhagem , Fosfoproteínas Fosfatases/genética , Sequenciamento do Exoma , Adulto Jovem
4.
Bioinformatics ; 33(5): 701-709, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27797778

RESUMO

Motivation: Most computational approaches for the analysis of omics data in the context of interaction networks have very long running times, provide single or partial, often heuristic, solutions and/or contain user-tuneable parameters. Results: We introduce local enrichment analysis (LEAN) for the identification of dysregulated subnetworks from genome-wide omics datasets. By substituting the common subnetwork model with a simpler local subnetwork model, LEAN allows exact, parameter-free, efficient and exhaustive identification of local subnetworks that are statistically dysregulated, and directly implicates single genes for follow-up experiments.Evaluation on simulated and biological data suggests that LEAN generally detects dysregulated subnetworks better, and reflects biological similarity between experiments more clearly than standard approaches. A strong signal for the local subnetwork around Von Willebrand Factor (VWF), a gene which showed no change on the mRNA level, was identified by LEAN in transcriptome data in the context of the genetic disease Cerebral Cavernous Malformations (CCM). This signal was experimentally found to correspond to an unexpected strong cellular effect on the VWF protein. LEAN can be used to pinpoint statistically significant local subnetworks in any genome-scale dataset. Availability and Implementation: The R-package LEANR implementing LEAN is supplied as supplementary material and available on CRAN ( https://cran.r-project.org ). Contacts: benno@pasteur.fr or tournier-lasserve@univ-paris-diderot.fr. Supplementary information: Supplementary data are available at Bioinformatics online.


Assuntos
Biologia Computacional/métodos , Redes Reguladoras de Genes , Software , Transcriptoma , Animais , Hemangioma Cavernoso do Sistema Nervoso Central/genética , Hemangioma Cavernoso do Sistema Nervoso Central/metabolismo , Humanos , Camundongos , Proteínas/genética , Fator de von Willebrand/genética
5.
J Med Genet ; 54(8): 550-557, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28343148

RESUMO

BACKGROUND: Moyamoya angiopathy (MMA) is characterised by a progressive stenosis of the terminal part of the internal carotid arteries and the development of abnormal collateral deep vessels. Its pathophysiology is unknown. MMA can be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions (moyamoya syndrome) including some Mendelian diseases. We aimed to investigate the genetic basis of moyamoya using a whole exome sequencing (WES) approach conducted in sporadic cases without any overt symptom suggestive of a known Mendelian moyamoya syndrome. METHODS: A WES was performed in four unrelated early-onset moyamoya sporadic cases and their parents (trios). Exome data were analysed under dominant de novo, autosomal recessive and X-linked hypotheses. A panel of 17 additional sporadic cases with early-onset moyamoya was available for mutation recurrence analysis. RESULTS: We identified two germline de novo mutations in CBL in two out of the four trio probands, two girls presenting with an infancy-onset severe MMA. Both mutations were predicted to alter the ubiquitin ligase activity of the CBL protein that acts as a negative regulator of the RAS pathway. These two germline CBL mutations have previously been described in association with a developmental Noonan-like syndrome and susceptibility to juvenile myelomonocytic leukaemia (JMML). Notably, the two mutated girls never developed JMML and presented only subtle signs of RASopathy that did not lead to evoke this diagnosis during follow-up. CONCLUSIONS: These data suggest that CBL gene screening should be considered in early-onset moyamoya, even in the absence of obvious signs of RASopathy.


Assuntos
Mutação em Linhagem Germinativa , Doença de Moyamoya/enzimologia , Doença de Moyamoya/genética , Proteínas Proto-Oncogênicas c-cbl/genética , Adolescente , Criança , Pré-Escolar , Feminino , Predisposição Genética para Doença , Humanos , Lactente , Masculino , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/patologia , Sequenciamento do Exoma
6.
Am J Hum Genet ; 88(6): 718-728, 2011 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-21596366

RESUMO

Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy.


Assuntos
Vasos Sanguíneos/anormalidades , Cromossomos Humanos X/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Proteínas de Membrana/genética , Doença de Moyamoya/genética , Neovascularização Fisiológica/genética , Animais , Sequência de Bases , Encéfalo/irrigação sanguínea , Enzimas Desubiquitinantes , Face/anormalidades , Feminino , Deleção de Genes , Técnicas de Silenciamento de Genes , Humanos , Masculino , Dados de Sequência Molecular , Doença de Moyamoya/diagnóstico , Doença de Moyamoya/patologia , Linhagem , Polimorfismo de Nucleotídeo Único , Proteínas Proto-Oncogênicas/genética , Peixe-Zebra/anormalidades , Peixe-Zebra/genética
7.
J Exp Med ; 208(9): 1835-47, 2011 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-21859843

RESUMO

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.


Assuntos
Proteínas de Transporte/genética , Malformações Vasculares do Sistema Nervoso Central/metabolismo , Hemorragia Cerebral/metabolismo , Endotélio Vascular/metabolismo , Proteínas dos Microfilamentos/genética , Animais , Proteínas de Transporte/metabolismo , Malformações Vasculares do Sistema Nervoso Central/genética , Malformações Vasculares do Sistema Nervoso Central/patologia , Malformações Vasculares do Sistema Nervoso Central/fisiopatologia , Cerebelo/irrigação sanguínea , Cerebelo/metabolismo , Cerebelo/patologia , Hemorragia Cerebral/genética , Hemorragia Cerebral/patologia , Hemorragia Cerebral/fisiopatologia , Modelos Animais de Doenças , Endotélio Vascular/patologia , Deleção de Genes , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/metabolismo , Retina/metabolismo , Retina/patologia , Retina/fisiopatologia
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