Titre :
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Congenital myasthenic syndromes : the 1293insG mutation in CHRNE is a founder ancestor mutation in patients from North Africa (abstract : congrès international de Myologie, 2005)
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contenu dans :
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Auteurs :
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Congrès international de myologie 2005 (International Congress of Myology 2005; 9-13 mai 2005; Nantes, France) ;
Richard P ;
Gaudon K ;
Haddad H ;
Koenig J ;
Bauche S ;
Grid D ;
Gouider-Khouja N ;
Mayer M ;
Desnuelle C ;
Pouget J ;
Hentati F ;
Eymard B ;
Hantaï D
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Type de document :
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Article
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Année de publication :
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2005
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Pages :
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p. 148
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Langues:
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Anglais
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Mots-clés :
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Afrique du Nord
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colloque
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consanguinité
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conseil génétique
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effet fondateur
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Europe (géographique)
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hétérozygote
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jonction neuromusculaire
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liaison génétique
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muscle squelettique
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mutation génétique
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sous-unité epsilon du récepteur nicotinique
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syndrome myasthénique congénital
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Résumé :
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Communication n° 235. Background: Congenital myasthenic syndromes (CMS) are hereditary disorders characterised by a defect in the neuromuscular transmission. Most cases showed recessive mode of inheritance and molecular analyses have shown that CMSs are caused by mutations in proteins of the neuromuscular junction. Twenty percent of European patients with a postsynaptic CMS carry mutations in CHRNE, the gene encoding for the epsilon subunit of the acetylcholine receptor (AChR). The observation that several patients originating from North Africa were all carriers of the 1293insG mutation, lead us to hypothesise for a founder mutation and to date the originating ancestor. Patients and methods: Eighty one individuals from 22 unrelated families originating from North Africa were analysed. The identification of the disease causing mutation was achieve by CHRNE sequencing. Determination of a founder effect was performed by analysis of 10 microsatellite markers spanning on 4.3Mb around the gene and 4 biallelic polymorphisms. Linkage disequilibrium between allele frequencies in affected patients and normal controls from the same origin was assessed by a chi-square test. Results: In 13 families out of the 22 analysed, the 1293insG mutation was identified at homozygous state in all affected patients according to the notion of consanguinity in families. The rate of mutation (60%) for this particular mutation was much higher than the involvement of the CHRNE gene in European families (20%). Analysis of extragenic microsatellites and intragenic polymorphisms allowed identifying a common core haplotypes of 63 kb and an extended haplotype. Comparison of allele frequencies between carriers and controls showed a strong linkage disequilibrium indicating a founder ancestor. Analysis of genetic recombination in affected individuals allowed estimating the number of generations when the mutation occurred. Conclusion: The high frequency of the CHRNE-1293insG mutation in patients originating from North Africa demonstrates a founder mutation. The identification of this mutation will facilitate the molecular approach in the genetic diagnosis of CMS patients from this origin and then to propose a more accurate genetic counselling in families. Supported by Assistance Publique-Hôpitaux de Paris (PHRC AOM1036), Inserm, GIS-Maladies Rares and AFM.
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