Intracellular transport of the DM‐20 bearing shaking pup ( shp ) mutation and its possible phenotypic consequences

Abstract

Paralytic tremor (pt) in rabbits and shaking pup (shp) in dogs are allelic dysmyelinated mutants of the proteolipid protein (Plp) gene. Both mutations affect the same amino acid, histidine36, which is replaced by glutamine in pt and by proline in shp. Phenotypic expression of these two mutations is very different. Paralytic tremor presents a much milder form of dysmyelination than shaking pup. The number of oligodendrocytes in the mutant rabbit is normal, while in the dog, the oligodendrocyte number is reduced due to early death or incomplete maturation. We have previously reported an abnormal intracellular transport of the PLPpt, whereas DM-20pt was normally transported to the cell membrane. In the present study, we show that the transport of the two isoforms containing the shp mutation is impaired in transfected Cos-7 cells. Cotransfecting cells with different ratios and combinations of mutated PLP and DM-20 cDNAs, we demonstrated that DM-20pt, but not DM-20shp, facilitates intracellular trafficking and integration into the plasma membrane of either of the two mutated PLPs. The phenotypic difference between these two allelic mutations can result from differences in DM-20 protein trafficking and sorting. These results show that the loss of function of PLP is not position-dependent but depends on the nature of the mutation.

Molecular pathways of oligodendrocyte apoptosis revealed by mutations in the proteolipid protein gene

“…Thus, the interruption of trafficking that we observe for all mutant forms of PLP highlights the extreme sensitivity of this protein to even subtle changes in primary structure, which correlates with disease but not disease severity. In contrast, we find a strong correlation between the accumulation of mutant forms of DM-20 in the ER and severe disease in patients Tosic et al, 1996Tosic et al, , 1997. To date, we have examined 17 disease-causing missense mutations that are present in both PLP and DM-20 and we find for all published patient case histories that only mutations associated with severe disease interrupt DM-20 trafficking and cause the protein to accumulate in the ER ( Table 2).…”

“…X X lation, the more severe is the effect on the cell because it cannot marshal sufficient resources to rid itself of defective polypeptides (Gow et al, 1994a(Gow et al, , b, 1998Gow and Lazzarini, 1996;Tosic et al, 1996Tosic et al, , 1997. This hypothesis relies minimally on assumptions and hypothetical functions of the protein that are either missing or gained but rather suggests a disease mechanism that is largely independent of the specific mutation or its position in the primary structure.…”

Quantifying the carrier female phenotype in Pelizaeus-Merzbacher disease

“…16,17,[35][36][37][38] Such mutations account for approximately 25% of families with Pelizaeus-Merzbacher disease. The hypothesis states that coding region mutations perturb the three-dimensional conformation of PLP1 gene products and disrupt their trafficking through the secretory pathway of oligodendrocytes leading to toxic accumulation in the endoplasmic reticulum.…”