[Role of P/Q calcium channel in familial hemiplegic migraine]

International audienceVoltage-dependent calcium channels constitute one of the main pathways of calcium entry into neurons. They are the principal actors of synaptic transmission by controlling the release of neurotransmitters. They also contribute to numerous other cell functions, such as gene expression or synaptogenesis. These channels, by their essential cell functions, are at the origin of numerous channelopathies resulting from mutations of the genes encoding their different subunits. Familial Hemiplegic Migraine (FHM) represents one such example of these channelopathies. In this human disease, genetic studies have demonstrated the implication of the CACNA1A gene in a type 1 form of FHM. This gene encodes for the Ca(v)2.1 subunit of P/Q calcium channels and is the target of numerous mutations affecting the properties of channel activity. The question on how discrete mutations of this gene are able to alter the activity of the channel and contribute to the physiopathology of FHM remains an open question. The functional characterization of mutated channels in various heterologous expression systems, as well as in vivo in an animal model, provides a molecular scheme of the physiopathology of FHM in which neurons, astrocytes and blood circulation act in concert

The Genetic Basis of Moyamoya Disease

Moyamoya disease (MMD) is a rare cerebrovascular disease characterized by progressive spontaneous bilateral occlusion of the intracranial internal cerebral arteries (ICA) and their major branches with compensatory capillary collaterals resembling a "puff of smoke" (Japanese: Moyamoya) on cerebral angiography. These pathological alterations of the vessels are called Moyamoya arteriopathy or vasculopathy and a further distinction is made between primary and secondary MMD. Clinical presentation depends on age and population, with hemorrhage and ischemic infarcts in particular leading to severe neurological dysfunction or even death. Although the diagnostic suspicion can be posed by MRA or CTA, cerebral angiography is mandatory for diagnostic confirmation. Since no therapy to limit the stenotic lesions or the development of a collateral network is available, the only treatment established so far is surgical revascularization. The pathophysiology still remains unknown. Due to the early age of onset, familial cases and the variable incidence rate between different ethnic groups, the focus was put on genetic aspects early on. Several genetic risk loci as well as individual risk genes have been reported; however, few of them could be replicated in independent series. Linkage studies revealed linkage to the 17q25 locus. Multiple studies on the association of SNPs and MMD have been conducted, mainly focussing on the endothelium, smooth muscle cells, cytokines and growth factors. A variant of the RNF213 gene was shown to be strongly associated with MMD with a founder effect in the East Asian population. Although it is unknown how mutations in the RNF213 gene, encoding for a ubiquitously expressed 591 kDa cytosolic protein, lead to clinical features of MMD, RNF213 has been confirmed as a susceptibility gene in several studies with a gene dosage-dependent clinical phenotype, allowing preventive screening and possibly the development of new therapeutic approaches. This review focuses on the genetic basis of primary MMD only

Regulation of β1 Integrin-Klf2-mediated angiogenesis by CCM proteins

International audienceGraphical Abstract Click here to download high resolution imag

GEN-O-MA project: an Italian network studying clinical course and pathogenic pathways of moyamoya disease—study protocol and preliminary results

Background: GENetics of mOyaMoyA (GEN-O-MA) project is a multicenter observational study implemented in Italy aimed at creating a network of centers involved in moyamoya angiopathy (MA) care and research and at collecting a large series and bio-repository of MA patients, finally aimed at describing the disease phenotype and clinical course as well as at identifying biological or cellular markers for disease progression. The present paper resumes the most important study methodological issues and preliminary results. Methods: Nineteen centers are participating to the study. Patients with both bilateral and unilateral radiologically defined MA are included in the study. For each patient, detailed demographic and clinical as well as neuroimaging data are being collected. When available, biological samples (blood, DNA, CSF, middle cerebral artery samples) are being also collected for biological and cellular studies. Results: Ninety-eight patients (age of onset mean ± SD 35.5 ± 19.6 years; 68.4% females) have been collected so far. 65.3% of patients presented ischemic (50%) and haemorrhagic (15.3%) stroke. A higher female predominance concomitantly with a similar age of onset and clinical features to what was reported in previous studies on Western patients has been confirmed. Conclusion: An accurate and detailed clinical and neuroimaging classification represents the best strategy to provide the characterization of the disease phenotype and clinical course. The collection of a large number of biological samples will permit the identification of biological markers and genetic factors associated with the disease susceptibility in Italy

Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

As revealed in a new model of cerebral cavernous malformations (CCM), the timing of ablation of Ccm genes determines whether or not CCM lesions arise in brain and retina venous beds

Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel

BackgroundDespite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies.ObjectiveTo develop guidelines for CCM management.MethodsThe Angioma Alliance ( www.angioma.org ), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol.ResultsOf 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%).ConclusionCurrent evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines

Bases moléculaires des angiomes caverneux héréditaires

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

IDENTIFICATION DES LOCUS DE PREDISPOSITION IMPLIQUES DANS LES FORMES FAMILIALES DE THYROIDITES AUTOIMMUNES (CRIBLAGE DU CHROMOSOME 1 (DES BIOL.MED.))

LYON1-BU Santé (693882101) / SudocSudocFranceF

IDENTIFICATION DU GENE CCM1 IMPLIQUE DANS LES CAVERNOMATOSES CEREBRALES FAMILIALES

LES CAVERNOMES CEREBRAUX SONT DES MALFORMATIONS VASCULAIRES DU SYSTEME NERVEUX CENTRAL. LEUR PREVALENCE EST ESTIMEE A 0.1% ; ENVIRON 20% DES CAS CORRESPONDENT A UNE MALADIE HEREDITAIRE A TRANSMISSION AUTOSOMIQUE DOMINANTE. EN 1995, UNE EQUIPE AMERICAINE AVAIT LOCALISE UN PREMIER GENE (CCM1) EN 7Q21. LA STRATEGIE QUE NOUS AVONS CHOISIE POUR AVANCER DANS LA COMPREHENSION DES MECANISMES PHYSIOPATHOLOGIQUES DE CETTE AFFECTION A ETE D'IDENTIFIER CE PREMIER GENE PAR CLONAGE POSITIONNEL. UNE ANALYSE DE LIAISON GENETIQUE CONDUITE SUR 36 FAMILLES NOUS A PERMIS DE CONFIRMER L'HETEROGENEITE GENETIQUE DE CETTE AFFECTION ET D'ESTIMER LA PROPORTION DE FAMILLES FRANCAISES LIEES A CE LOCUS A ENVIRON 65%. LA CARTOGRAPHIE GENETIQUE HAUTE-RESOLUTION NOUS A PERMIS UNE REDUCTION MODESTE DE L'INTERVALLE. UNE APPROCHE BIO-INFORMATIQUE S'APPUYANT SUR LES DONNEES D'UN CONTIG DE CHROMOSOMES ARTIFICIELS DE LEVURES NOUS A PERMIS DE RECONSTITUER 80% DE LA SEQUENCE DE L'INTERVALLE. EN UTILISANT DES METHODES BIOINFORMATIQUES ET MOLECULAIRES, NOUS AVONS ETABLI UNE CARTE TRANSCRIPTIONNELLE DE LA REGION CCM1 ET IDENTIFIE UN TOTAL DE 53 TRANSCRITS POTENTIELS INCLUANT 8 GENES CONNUS CHEZ L'HOMME OU DANS UNE AUTRE ESPECE. LE CRIBLAGE DE 5 DE CES GENES NOUS A PERMIS D'IDENTIFIER CCM1 COMME ETANT LE GENE CODANT POUR LA PROTEINE KRIT1. TOUTES LES MUTATIONS IDENTIFIEES RESULTAIENT EN UNE PROTEINE PUTATIVE TRONQUEE DE SA PARTIE C-TERMINALE, REGION D'INTERACTION AVEC LA PROTEINE RAP1A. LA NATURE DES MUTATIONS OBSERVEES DANS LES FAMILLES POUVAIT EVOQUER SOIT UN MECANISME DE PERTE DE FONCTION, SOIT UN EFFET DOMINANT-NEGATIF. IL EST MAINTENANT NECESSAIRE DE PRECISER LE PROFIL D'EXPRESSION TISSULAIRE DE CETTE PROTEINE KRIT1 DANS LES TISSUS NORMAUX ET PATHOLOGIQUES, SA LOCALISATION SUB-CELLULAIRE ET DE METTRE AU POINT UN MODELE IN VITRO AINSI QU'UN MODELE ANIMAL POUR COMPRENDRE LES EFFETS DES MUTATIONS DECRITES ET MIEUX APPREHENDER LES MECANISMES PHYSIOPATHOLOGIQUES DE CETTE AFFECTION.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF