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NEUROLOGY 2008;71:1967-1972
© 2008 American Academy of Neurology

The CHRNE 1293insG founder mutation is a frequent cause of congenital myasthenia in North Africa

P. Richard, PhD, K. Gaudon, MS, H. Haddad, MD, A. Ben Ammar, MS, E. Genin, PhD, S. Bauché, MS, M. Paturneau-Jouas, PhD, J. S. Müller, PhD, H. Lochmüller, MD, D. Grid, MD, A. Hamri, MD, S. Nouioua, MD, M. Tazir, MD, M. Mayer, MD, C. Desnuelle, MD, A. Barois, MD, B. Chabrol, MD, J. Pouget, MD, J. Koenig, PhD, N. Gouider-Khouja, MD, F. Hentati, MD, B. Eymard, MD, PhD and D. Hantaï, MD, PhD

Authors’ affiliations are listed at the end of the article.
AUTHORS’ AFFILIATIONS From AP-HP, UF Cardiogénétique et Myogénétique (P.R., K.G.), Inserm, U582, Institut de Myologie (P.R., K.G., H.H., A.B.A., S.B., M.P.-J., J.K., B.E., D.H.), and AP-HP, Centre de Référence en Pathologie Neuromusculaire Paris-Est (H.H., S.B., B.E., D.H.), GH Pitié Salpêtrière, Paris; UPMC Université Paris 06 (P.R., K.G., H.H., A.B.A., S.B., M.P.-J., J.K., B.E., D.H.), France; Institut de Neurologie (A.B.A., N.G.-K., F.H.), La Rabta, Tunis; Université Tunis El Manar (A.B.A., N.G.-K., F.H.), Tunisia; Inserm, U535, Génétique Épidémiologique et Structure des Populations Humaines (E.G.), Hôpital Paul Brousse, Villejuif, France; Institute of Human Genetics (J.S.M., H.L.), University of Newcastle, UK; Généthon (D.G.), Évry, France; Hôpital Benbadis (A.H.), Service de Neurologie, Constantine; Hôpital Mustapha (S.N., M.T.), Service de Neurologie, Alger, Algeria; AP-HP (M.M.), Service de Neuropédiatrie, Hôpital Saint Vincent de Paul, Paris; Service de Médecine Physique et Réadaptation des Maladies Neuromusculaires (C.D.), Hôpital l’Archet, Nice; Hôpital Raymond Poincaré (A.B.), Garches; Service d’Anatomie Pathologique et de Neuropathologie (B.C.) and Service de Neurologie et des Maladies Neuromusculaires (J.P.), Hôpital La Timone, Marseille; and Université Bordeaux 2 (J.K.), France.

Address correspondence and reprint requests to Dr. Daniel Hantaï, Inserm, U582, 47 Boulevard de l’Hopital, Paris, France 75651 d.hantai{at}institut-myologie.org

Objective: Mutations in various genes of the neuromuscular junction cause congenital myasthenic syndrome (CMS). A single truncating mutation ({varepsilon}1293insG) in the acetylcholine receptor epsilon subunit gene (CHRNE) was most often identified in CMS families originating from North Africa and was possibly a founder mutation.

Methods: Twenty-three families were studied with an early onset form of CMS and originating from Tunisia, Algeria, Morocco, and Libya. Screening for the mutation {varepsilon}1293insG was performed by direct sequencing. Haplotype analysis was done with 9 (CA)n repeat microsatellite markers and 6 SNPs flanking {varepsilon}1293insG on chromosome 17p13-p12. Dating was calculated using the ESTIAGE method for rare genetic diseases.

Results: The {varepsilon}1293insG mutation was identified in 14 families (about 60% of the initial 23). The expression of the CMS in affected members of these families was relatively homogeneous, without fetal involvement or being life-threatening, with moderate hypotonia and oculobulbar involvement, mild and stable disease course, and good response to cholinesterase inhibitors. Haplotype analysis revealed a common conserved haplotype encompassing a distance of 63 kb. The estimated age of the founder event was at least 700 years.

Conclusions: These results strongly support the hypothesis that {varepsilon}1293insG derives from an ancient single founder event in the North African population. Identification of founder mutations in isolated or inbred populations may have important implications in the context of molecular diagnosis and genetic counseling of patients and families by detection of heterozygous carriers.

Abbreviations: CMS = congenital myasthenic syndrome; MRCA = most recent common ancestor.

Supported by Assistance Publique-Hôpitaux de Paris (PHRC AOM 1036), Réseaux Inserm, ANR-Maladies Rares, Association Française contre les Myopathies, Comité Mixte Franco-Tunisien pour la Coopération Universitaire (CMCU Project #05G0809), and a Contrat d’Interface AP-HP Inserm (to D.H.). J.S.M. is supported by a postdoctoral fellowship of the Deutsche Forschungsgemeinschaft (Bonn, Germany, MU2840/1-1).

Disclosure: The authors report no disclosures.

Received June 23, 2008. Accepted in final form September 15, 2008.






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