X–linked spastic paraplegia and Pelizaeus–Merzbacher disease are allelic disorders at the proteolipid protein locus

Three forms of X–linked spastic paraplegia (SPG) have been defined. One locus (SPG 1) maps to Xq28 while two clinically distinct forms map to Xq22 (SPG2). A rare X–linked dysmyelinating disorder of the central nervous system, Pelizaeus–Merzbacher disease (PMD), has also been mapped to Xq21–q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20. While narrowing the genetic interval containing SPG2 in a large pedigree, we found that PLP was the closest marker to the disease locus, implicating PLP as a possible candidate gene. We have found that a point mutation (His139Tyr) in exon 3B of an affected male produces a mutant PLP but a normal DM20,and segregates with the disease (Zmax=6.63, θ=0.00). It appears, therefore, that SPG2 and PMD are allelic disorders.