Genotype-phenotype correlation in inherited brain myelination defects due to proteolipid protein gene mutations

Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2) are X-linked developmental defects of myelin formation affecting the central n ervous system (CNS). They differ clinically in the onset and severity of th e motor disability but both are allelic to the proteolipid protein gene (PL P), which encodes the principal protein components of CNS myelin, PLP and i ts spliced isoform, DM20. We investigated 52 PMD and 28 SPC families withou t large PLP duplications or deletions by genomic PCR amplification and sequ encing of the PLP gene. We identified 29 and 4 abnormalities respectively. Patients with PLP mutations presented a large range of disease severity, wi th a continuum between severe forms of PMD, without motor development, to p ure forms of SPC. Clinical severity was found to be correlated with the nat ure of the mutation, suggesting a distinct strategy for detection of PLP po int mutations between severe PMD, mild PMD and SPC. Single amino-acid chang es in highly conserved regions of the DM20 protein caused the most severe f orms of PMD. Substitutions of less conserved amino acids, truncations, abse nce of the protein and PLP-specific mutations caused the milder forms of PM D and SPG. Therefore, the interactions and stability of the mutated protein s has a major effect on the severity of PLP-related diseases.