DUPLICATION OF THE PROTEOLIPID PROTEIN GENE IS THE MAJOR CAUSE OF PELIZAEUS-MERZBACHER-DISEASE

Background/Objective: Pelizaeus-Merzbacher disease (PMD), an X-linked recessive dysmyelination disorder, is caused by mutations in the prote olipid protein (PLP) gene. However, missense mutations were only found in a fraction of PMD patients, even in families that showed linkage w ith the PLP locus on Xq22. Here we describe the use of an extended pro tocol that includes screening for both missense mutations and duplicat ions. Method: Two groups of patients were analyzed, one group with 10 independent PMD families and one group with 24 sporadic patients suspe cted of PMD. Missense mutations in the PLP gene were identified by seq uencing. PLP gene duplications were detected by quantitative polymeras e chain reaction and/or Southern blot analysis. Results: Sequencing of the PLP gene revealed four mutations in group 1 and one mutation in g roup 2. However, inclusion of duplication analysis in the screening pr otocol 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. Furtherm ore, it appears that the phenotype resulting from PLP duplications is relatively mild, and that many probands are nontypical PMD patients.