Exon Deletion in the Non-catalytic Domain of eIF2Bɛ Due to a Splice Site Mutation Leads to Infantile Forms of CACH/VWM with Severe Decrease of eIF2B GEF Activity

Authors

  • L. Horzinski,

    1. INSERM UMR384, Faculté de Médecine, 28 place Henri Dunant, F-63003 Clermont-Ferrand, France
    2. Université Clermont1, UFR Médecine, 28 place Henri Dunant, F-63003 Clermont-Ferrand, France
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  • C. Gonthier,

    1. INSERM UMR384, Faculté de Médecine, 28 place Henri Dunant, F-63003 Clermont-Ferrand, France
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  • D. Rodriguez,

    1. Assistance Publique-Hôpitaux de Paris, Hôpital Armand Trousseau, Service de Neuropédiatrie, 26 avenue du Dr Arnold Netter, F-75012 Paris, France
    2. INSERM U546, 105 boulevard de l'Hôpital, F-75013 Paris, France
    3. Université Pierre et Marie Curie-Paris 6, F-75000 Paris, France
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  • C. Scherer,

    1. Hôpital Bel-Air, Service de Neurologie, 1-3 rue du Frescati,F-57126 Thionville, France
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  • O. Boespflug-Tanguy,

    1. INSERM UMR384, Faculté de Médecine, 28 place Henri Dunant, F-63003 Clermont-Ferrand, France
    2. Université Clermont1, UFR Médecine, 28 place Henri Dunant, F-63003 Clermont-Ferrand, France
    3. CHU de Clermont-Ferrand, Service de Génétique Médicale, Centre de Référence Leucodystrophies, Hôpital Hotel-Dieu, F-63058 Clermont-Ferrand, France
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  • A. Fogli

    1. Université Clermont1, UFR Médecine, 28 place Henri Dunant, F-63003 Clermont-Ferrand, France
    2. CHU de Clermont-Ferrand, Service de Biochimie Médicale et Biologie Moléculaire, F-63058 Clermont-Ferrand, France
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*Corresponding author: Dr. Anne Fogli, INSERM UMR384, Faculté de Médecine, 28 place Henri Dunant, 63000 Clermont-Ferrand. Phone: 33 4 73 44 86 57. Fax: 33 4 73 17 83 83. E-mail: anne.fogli@inserm.u-clermont1.fr

Summary

The CACH/VWM syndrome is an autosomal recessive leukodystrophy characterized by a broad spectrum of clinical presentations and by diffuse cavitary degeneration of the white matter on MRI. Mutations responsible for this disorder are missense or frameshift mutations occurring in the five genes (EIF2B1-5) that encode the translation eukaryotic initiation factor eIF2B. We found that a patient with infantile CACH/VWM carries a mutation in the acceptor splice site of EIF2B5 exon 6. In lymphoblastoid cells of the patient, we detected an abnormal EIF2B5 transcript in which exon 6 was absent, however, the predicted protein product lacking part of the non-catalytic domain encoded by exon 6 was not detected. The eIF2B GEF activity was severely decreased. These data support the importance of the non-catalytic domain of the eIF2Bɛ subunit in the eIF2B complex formation and activity.

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