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From the Department of Human Genetics (Drs. Sistermans, de Coo, and Van Oost, and I.J. De Wijs), University Hospital Nijmegen; the Department of Pediatric Neurology (Dr. de Coo), University Hospital Rotterdam; and the Department of Clinical Sciences of Companion Animals (Dr. Van Oost), University of Utrecht, The Netherlands.
Address correspondence and reprint requests to Dr. Erik Sistermans, Department of Human Genetics, University Hospital Nijmegen, PO Box 9101,6500 HB 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 wo 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 andlor 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.
Received November 17, 1997. Accepted in final form January 30, 1998.
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