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. On e locus (SPG 1) maps to Xq28 while two clinically distinct forms map t o Xq22 (SPG2). A rare X-linked dysmyelinating disorder of the central nervous system, Pelizaeus-Merzbacher disease (PMD), has also been mapp ed to Xq21-q22, and is caused by mutations in the proteolipid protein gene (PLP) which encodes two myelin proteins, PLP and DM20. While narr owing the genetic interval containing SPG2 in a large pedigree, we fou nd that PLP was the closest marker to the disease locus, implicating P LP 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, theta=0.00). It appears, therefore, that SPG2 and PMD are allelic disorders.