HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 55, Number 8, October 24, 2000 Supplementary Data Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hobson, G. M. Articles by Marks, H. G. Search for Related Content PubMed PubMed Citation Articles by Hobson, G. M. Articles by Marks, H. G.

Mutations in noncoding regions of the proteolipid protein gene in Pelizaeus–Merzbacher disease

From the Department of Research, Alfred I. duPont Hospital for Children (Drs. Hobson and Funanage, and N.C. Stowell), Wilmington, DE; Department of Pediatrics (Drs. Hobson and Funanage) and Jefferson Medical College (A.P. Davis), Thomas Jefferson University, Philadelphia, PA; New York University School of Medicine (Dr. Kolodny), New York, NY; Department of Human Genetics (Dr. Sistermans), University Medical Center Nijmegen, the Netherlands; Department of Neurology, University Hospital Rotterdam (Dr. de Coo), the Netherlands; and Nemours Children’s Clinic (Dr. Marks), Ft. Myers, FL.

Address correspondence and reprint requests to Dr. Grace M. Hobson, Research Department, Alfred I. duPont Hospital for Children, P.O. Box 269, Wilmington, DE 19899; e-mail: ghobson{at}nemours.org

BACKGROUND: Pelizaeus–Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of the proteolipid protein (PLP) gene are found in most patients.

OBJECTIVE: To describe five patients with PMD who have mutations in noncoding regions of the PLP gene.

METHODS: Quantitative multiplex PCR and Southern blot analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene.

RESULTS: Duplication of the PLP gene was ruled out, and mutations were identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IVS6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 months and progressive spastic ataxia at 18 months was found to have a 19–base pair (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19-bp deletion, are in intron 3, which is involved in PLP/DM20 alternative splice site selection.

CONCLUSIONS: Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.

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]

				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]

				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]

				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]