Osaka Hitoshi, Koizume Shiro, Aoyama Haruhiko, Iwamoto Hiroko, Kimura Seiji, Nagai Jun-Ichi, Kurosawa Kenji, Yamashita Sumimasa
Division of Neurology, Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama 232-855, Japan.
Brain Dev. 2010 Oct;32(9):703-7. doi: 10.1016/j.braindev.2009.11.004. Epub 2009 Dec 21.
We present the case of a 26 year-old man who developed normally until he began having difficulty walking at age 12. He subsequently became unable to stand at 15 years old and exhibited mental regression and generalized tonic convulsions by age 20. Magnetic resonance imaging revealed incomplete myelination of cerebral white matter, which resembled that of Pelizaeus-Merzbacher disease. By sequencing the proteolipid protein 1 (PLP1) gene, we found a novel mutation (c.352_353delAG (p.Gly130fs)) in the latter half of exon 3 (exon 3B) that is spliced out in the DM20 isoform. Exon 3B mutations are known to cause a mild phenotype since they do not disturb DM20 production. Mutations that truncate PLP1 correlate with a mild phenotype by activating the nonsense-mediated decay mechanism that specifically detects and degrades mRNAs containing a premature termination codon. This attenuates the production of toxic mutant PLP1. The very mild presentation in the present case seems to be derived from the unique nature of the mutation, which preserves DM20 production and decreases mutant PLP1.
我们报告了一名26岁男性的病例，该患者在12岁开始出现行走困难之前发育正常。随后，他在15岁时无法站立，并在20岁时出现智力衰退和全身性强直惊厥。磁共振成像显示脑白质髓鞘形成不全，类似于佩利措伊斯-梅茨巴赫病。通过对蛋白脂蛋白1（PLP1）基因进行测序，我们在第3外显子后半部分（外显子3B）发现了一个新的突变（c.352_353delAG (p.Gly130fs)），该突变在DM20异构体中被剪接掉。已知外显子3B突变会导致轻度表型，因为它们不会干扰DM20的产生。截断PLP1的突变通过激活无义介导的衰变机制与轻度表型相关，该机制可特异性检测和降解含有过早终止密码子的mRNA。这会减少有毒突变体PLP1的产生。本病例中非常轻微的表现似乎源于该突变的独特性质，即保留了DM20的产生并减少了突变体PLP1。
