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Pelizaeus‐Merzbacher disease: Three novel mutations and implication for locus heterogeneity
Author(s) -
Osaka Hitoshi,
Kawanishi Chiaki,
Inoue Ken,
Onishi Hideki,
Kobayashi Takuya,
Sugiyama Naoya,
Kosaka Kenji,
Nezu Atsuo,
Fujii Katsunori,
Sugita Katsuo,
Kodama Kazuo,
Murayama Keiko,
Murayama Shigeo,
Kanazawa Ichiro,
Kimura Seiji
Publication year - 1999
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/1531-8249(199901)45:1<59::aid-art11>3.0.co;2-3
Subject(s) - locus (genetics) , genetics , biology , gene , genetic heterogeneity , proteolipid protein 1 , degenerative disease , mutation , central nervous system disease , phenotype , neuroscience , myelin , myelin basic protein , central nervous system
Abstract 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 prevented the toxicity associated with a gain of function mutation. Moreover, in one family 3 patients exhibited a intragenic polymorphism that did not segregate with the disease, suggesting a locus heterogeneity for Pelizaeus‐Merzbacher disease. Ann Neurol 1999;45:59–64