A DUPLICATED PLP GENE CAUSING PELIZAEUS-MERZBACHER DISEASE DETECTED BY COMPARATIVE MULTIPLEX PCR

Pelizaeus-Merzbacher disease (PMD) is an X-linked dysmyelinating disor der caused by abnormalities in the proteolipid protein (PLP) gene, whi ch is essential for oligodendrocyte differentiation and CNS myelin for mation. Although linkage analysis has shown the homogeneity at the PLP locus in patients with PMD, exonic mutations in the PLP gene have bee n identified in only 10%-25% of all cases, which suggests the presence of other genetic aberrations, including gene duplication. In this stu dy, we examined five families with PMD not carrying exonic mutations i n PLP gene, using comparative multiplex PCR (CM-PCR) as a semiquantita tive assay of gene dosage. PLP gene duplications were identified in fo ur families by CM-PCR and confirmed in three families by densitometric RFLP analysis. Because a homologous myelin protein gene, PMP22, is du plicated in the majority of patients with Charcot-Marie-Tooth 1A, PLP gene overdosage may be a important genetic abnormality in PMD and affe ct myelin formation.