Pelizaeus-Merzbacher disease: Three novel mutations and implication for locus heterogeneity

We report a mutational and polymorphic analysis of the proteolipid protein gene in members of 27 Japanese families with Pelizaeus-Merzbacher disease. We found causative mutations in 6 members of 27 families (22.2%); 5 of the 6 mutations, including two novel mutations, Leu(45)Arg and 231 + 2T --> G, resulted in the typically severe clinical symptoms. Paradoxically, the Cys( 219)Tyr mutation, presumed to disrupt the tertiary structure of proteolipid protein by removing the disulfide bond between Cys(200) and Cys(219), was associated with a mild clinical presentation wherein the patient could walk with assistance and speak. It was inferred that the structural change prev ented the toxicity associated with a gain of function mutation. Moreover, i n one family 3 patients exhibited a intragenic polymorphism that did not se gregate with the disease, suggesting a locus heterogeneity for Pelizaeus-Me rzbacher disease.