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 (Z_max=6.63, =0.00). It appears, therefore, that SPG2 and PMD are allelic disorders.

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