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PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: identification of one partial triplication and two partial deletions of PLP1

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Abstract

The proteolipid protein 1 (PLP1) gene is known to be mutated in the X-linked disorders of myelin formation Pelizaeus–Merzbacher disease (PMD) and spastic paraplegia type 2. The most commonly found PLP1 mutations are gene duplications (60–70%) and point mutations (20%). About 20% of patients with a PMD phenotype do not present identified PLP1 mutation, thus suggesting genetic heterogeneity and/or undetected PLP1 abnormalities. Except the recently described MLPA screening the seven exonic regions, the currently used techniques to quantify PLP1 gene copy number do not investigate small intragenic PLP1 rearrangements. Using the multiplex amplifiable probe hybridization (MAPH) technique, we looked simultaneously for intragenic rearrangements along the PLP1 gene (exonic and regulatory regions) and for rearrangements in the GPM6B candidate gene (a member of the proteolipid protein family). We tested 262 hypomyelinating patients: 56 PLP1 duplicated patients, 1 PLP1 triplicated patient, and 205 patients presenting a leukodystrophy of undetermined origin with brain MRI suggesting a defect in myelin formation. Our results show that MAPH is an alternative reliable technique for diagnosis of PLP1 gene copy number. It allows us (1) to demonstrate that all PLP1 duplications previously found encompass the whole gene, (2) to establish that copy number changes in GPM6B and intragenic duplications of PLP1 are very unlikely to be involved in the etiology of UHL, and (3) to identify one partial triplication and two partial deletions of PLP1 in patients presenting with a PMD phenotype.

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Acknowledgements

We are grateful to the members of the clinical European Network on Brain Dysmyelinating Disease (ENBDD) and of LeukoFrance Network who have provided us with samples from their patients: M. Baethmann, T. Billette, B. Chabrol, D. Chaigne, J.M. Cuisset, I. Desguerre, J. Gartner, F. Hanefeld, A. Kohlschutter, P. Landrieu, J.M. Lopes-Terradas, M. Mayer, J.M. Prats-Vinas, D. Rating, R. Surtees, G. Uziel, L. Vallee, T. Voit with the collaboration of M.A. Barthez-Carpentier, A. Brady, P. Burkart, G. Cioni, B. Dan, G. Echenne, P. Evrard, B. Fontaine, C. Hübner, I. Krägeloh-Mann, J.P. Misson, J. Motte, A. Munich, J.M. Pedespan, B. Plecko, G. Ponsot, F. Rivier, G. Sebire, C. Steen, H. Steinbock, M. Troncoso, C. Vahule, R. Van Coster, L. Van Maldergen, C. Yalcinkaya. This study was supported by the European Leucodystrophy Association, the Foundation for Medical Research (ARS 2000), and the Jean-Pierre and Nancy Boespflug myopathic research foundation.

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Authors and Affiliations

  1. INSERM U 384, Faculté de Médecine, Place Henri Dunant, 63000, Clermont-Ferrand, France

    Patricia Combes, Marie-Noelle Bonnet-Dupeyron, Fernande Gauthier-Barichard, Odile Boespflug-Tanguy & Catherine Vaurs-Barrière

  2. Developmental and Metabolic Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

    Raphael Schiffmann

  3. Department of Molecular Medicine, Ospedale Pediatrico Bambino Gesu, Scientific Institute, IRCCS, Rome, Italy

    Enrico Bertini

  4. INSERM U546, Faculté de la Pitié Salpétrière, 105 boulevard de l’Hôpital, 75013, Paris, France

    Diana Rodriguez

  5. Institute of Genetics, Queen’s Medical Centre, University of Nottingham, Nottingham, NG7 2UH, UK

    John A. L. Armour

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  1. Patricia Combes
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  2. Marie-Noelle Bonnet-Dupeyron
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Correspondence to Odile Boespflug-Tanguy.

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Combes, P., Bonnet-Dupeyron, MN., Gauthier-Barichard, F. et al. PLP1 and GPM6B intragenic copy number analysis by MAPH in 262 patients with hypomyelinating leukodystrophies: identification of one partial triplication and two partial deletions of PLP1 . Neurogenetics 7, 31–37 (2006). https://doi.org/10.1007/s10048-005-0021-1

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