Different mutations in the same codon of the proteolipid protein gene, PLP, way help in correlating genotype with phenotype in Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2)

Pelizaeus-Merzbacher disease/X-linked spastic paraplegia (PMD/SPG2) compris es a spectrum of diseases that range from severe to quite mild. The reasons for the variation in severity are not obvious, but suggested explanations include the extent of disruption of the transmembrane portion of the proteo lipid protein caused by certain amino acid substitutions and interference w ith the trafficking of the PLP molecule in oligodendrocytes. Four codons in which substitution of more than one amino acid has occurred are available for examination of clinical and potential structural manifestations: Valine 165 to either glutamate or glycine, leucine 045 to either proline or argini ne, aspartate 202 to asparagine or histidine, and leucine 223 to isoleucine or proline. Three of these mutations, Val165Gly, Leu045Pro, and Leu223Ile have not been described previously in humans. The altered amino acids appea r in the A-B loop, C helix, and C-D loop, respectively. me describe clinica lly patients with the mutations T494G (Val165Gly), T134C (Leu045Pro), and C 667A (Leu223Ile). We discuss also the previously reported mutations Asp202A sn and Asp202His. me have calculated the changes in hydrophobicity of short sequences surrounding some of these amino acids and compared the probable results of the changes in transmembrane structure of the proteolipid protei n for the various mutations with the clinical data available on the patient s. While the Val165Glu mutation, which is expected to produce disruption of a transmembrane loop of the protein, produces more severe disease than doe s Val165Gly, no particular correlation with hydrophobicity is found for the other mutations. As these are not in transmembrane domains, other factors such as intracellular transport or interaction between protein chains durin g myelin formation are probably at work. (C) 1999 Wiley-Liss, Inc.