Neurology, Vol 50, Issue 6 1749-1754, Copyright © 1998 by American Academy of Neurology

ARTICLES

Duplication of the proteolipid protein gene is the major cause of Pelizaeus-Merzbacher disease

EA Sistermans, RF de Coo, IJ De Wijs and BA Van Oost
Department of Human Genetics, University Hospital Nijmegen, The Netherlands.

BACKGROUND/OBJECTIVE: Pelizaeus-Merzbacher disease (PMD), an X-linked recessive dysmyelination disorder, is caused by mutations in the proteolipid protein (PLP) gene. However, missense mutations were only found in a fraction of PMD patients, even in families that showed linkage with the PLP locus on Xq22. Here we describe the use of an extended protocol that includes screening for both missense mutations and duplications. METHOD: Two groups of patients were analyzed, one group with 10 independent PMD families and one group with 24 sporadic patients suspected of PMD. Missense mutations in the PLP gene were identified by sequencing. PLP gene duplications were detected by quantitative polymerase chain reaction and/or Southern blot analysis. RESULTS: Sequencing of the PLP gene revealed four mutations in group 1 and one mutation in group 2. However, inclusion of duplication analysis in the screening protocol raised the amount of mutations found in group 1 from 40 to 90%, and in group 2 from 4 to 25%. CONCLUSIONS: These results demonstrate that duplications of the PLP gene are the major cause of PMD. Furthermore, it appears that the phenotype resulting from PLP duplications is relatively mild, and that many probands are nontypical PMD patients.

This article has been cited by other articles:

				M. C. Tuason, A. Rastikerdar, T. Kuhlmann, C. Goujet-Zalc, B. Zalc, S. Dib, H. Friedman, and A. Peterson Separate Proteolipid Protein/DM20 Enhancers Serve Different Lineages and Stages of Development J. Neurosci., July 2, 2008; 28(27): 6895 - 6903. [Abstract] [Full Text] [PDF]

				J. A. Lee, K. Inoue, S. W. Cheung, C. A. Shaw, P. Stankiewicz, and J. R. Lupski Role of genomic architecture in PLP1 duplication causing Pelizaeus-Merzbacher disease Hum. Mol. Genet., July 15, 2006; 15(14): 2250 - 2265. [Abstract] [Full Text] [PDF]

				I. Warshawsky, O. B. Chernova, C. A. Hubner, R. Stindl, M. Henneke, A. Gal, and M. R. Natowicz Multiplex Ligation-Dependent Probe Amplification for Rapid Detection of Proteolipid Protein 1 Gene Duplications and Deletions in Affected Males and Carrier Females with Pelizaeus-Merzbacher Disease Clin. Chem., July 1, 2006; 52(7): 1267 - 1275. [Abstract] [Full Text] [PDF]

				N. I. Wolf, E. A. Sistermans, M. Cundall, G. M. Hobson, A. P. Davis-Williams, R. Palmer, P. Stubbs, S. Davies, M. Endziniene, Y. Wu, et al. Three or more copies of the proteolipid protein gene PLP1 cause severe Pelizaeus-Merzbacher disease Brain, April 1, 2005; 128(4): 743 - 751. [Abstract] [Full Text] [PDF]

				N Muncke, B S Wogatzky, M Breuning, E A Sistermans, V Endris, M Ross, D Vetrie, C E Catsman-Berrevoets, and G Rappold Position effect on PLP1 may cause a subset of Pelizaeus-Merzbacher disease symptoms J. Med. Genet., December 1, 2004; 41(12): e121 - e121. [Full Text] [PDF]

				N. I. Wolf, M. A.A.P. Willemsen, U. F. Engelke, M. S. van der Knaap, P. J.W. Pouwels, I. Harting, J. Zschocke, E. A. Sistermans, D. Rating, and R. A. Wevers Severe hypomyelination associated with increased levels of N-acetylaspartylglutamate in CSF Neurology, May 11, 2004; 62(9): 1503 - 1508. [Abstract] [Full Text] [PDF]

				L. D. Hudson Pelizaeus-Merzbacher Disease and Spastic Paraplegia Type 2: Two Faces of Myelin Loss From Mutations in the Same Gene J Child Neurol, September 1, 2003; 18(9): 616 - 624. [Abstract] [PDF]

				J. Takanashi, K. Inoue, M. Tomita, A. Kurihara, F. Morita, H. Ikehira, S. Tanada, E. Yoshitome, and Y. Kohno Brain N-acetylaspartate is elevated in Pelizaeus-Merzbacher disease with PLP1 duplication Neurology, January 22, 2002; 58(2): 237 - 241. [Abstract] [Full Text] [PDF]

				A. K. Percy Pelizaeus-Merzbacher disease: Splice sites are nice sites for disease expression Neurology, October 24, 2000; 55(8): 1072 - 1073. [Full Text] [PDF]

				G. M. Hobson, A. P. Davis, N. C. Stowell, E. H. Kolodny, E. A. Sistermans, I. F. M. de Coo, V. L. Funanage, and H. G. Marks Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus-Merzbacher disease Neurology, October 24, 2000; 55(8): 1089 - 1096. [Abstract] [Full Text] [PDF]

				D. A. Yool, J. M. Edgar, P. Montague, and S. Malcolm The proteolipid protein gene and myelin disorders in man and animal models Hum. Mol. Genet., April 1, 2000; 9(6): 987 - 992. [Abstract] [Full Text] [PDF]

				J.-i. Takanashi, K. Sugita, Y. Tanabe, K. Nagasawa, K. Inoue, H. Osaka, and Y. Kohno MR-Revealed Myelination in the Cerebral Corticospinal Tract as a Marker for Pelizaeus-Merzbacher's Disease with Proteolipid Protein Gene Duplication AJNR Am. J. Neuroradiol., November 1, 1999; 20(10): 1822 - 1828. [Abstract] [Full Text]

				J. Garbern, F. Cambi, M. Shy, and J. Kamholz The Molecular Pathogenesis of Pelizaeus-Merzbacher Disease Arch Neurol, October 1, 1999; 56(10): 1210 - 1214. [Full Text] [PDF]