Additional copies of the proteolipid protein gene causing Pelizaeus-Merzbacher disease arise by separate integration into the X chromosome

The proteolipid protein gene (PLP) is normally present at chromosome Xq22. Mutations and duplications of this gene are associated with Pelizaeus-Merzb acher disease (PMD). Here we describe two new families in which males affec ted with PMD were found to have a copy of PLP on the short arm of the X chr omosome, in addition to a normal copy on Xq22. In the first family, the ext ra copy was first detected by the presence of heterozygosity of the AhaII d imorphism within the PLP gene. The results of FISH analysis showed an addit ional copy of PLP in Xp22.1, although no chromosomal rearrangements could b e detected by standard karyotype analysis. Another three affected males fro m the family had similar findings. In a second unrelated family with signs of PMD, cytogenetic analysis showed a pericentric inversion of the X chromo some. In the inv(X) carried by several affected family members, FISH showed PLP signals at Xp11.4 and Xq22. A third family has previously been reporte d, in which affected members had an extra copy of the PLP gene detected at Xq26 in a chromosome with an otherwise normal banding pattern. The identifi cation of three separate families in which PLP is duplicated at a noncontig uous site suggests that such duplications could be a relatively common but previously undetected cause of genetic disorders.