Hobson G M, Davis A P, Stowell N C, Kolodny E H, Sistermans E A, de Coo I F, Funanage V L, Marks H G
Department of Research, Alfred I. duPont Hospital for Children, Wilmington, DE 19899, USA.
Neurology. 2000 Oct 24;55(8):1089-96. doi: 10.1212/wnl.55.8.1089.
Pelizaeus-Merzbacher disease (PMD) is an X-linked recessive dysmyelinating disorder of the CNS. Duplications or point mutations in exons of the proteolipid protein (PLP) gene are found in most patients.
To describe five patients with PMD who have mutations in noncoding regions of the PLP gene.
Quantitative multiplex PCR and Southern blot analyses were used to detect duplication of the PLP gene, and DNA sequence analysis, including exon-intron borders, was used to detect mutation of the PLP gene.
Duplication of the PLP gene was ruled out, and mutations were identified in noncoding regions of five patients in four families with PMD. In two brothers with a severe form of PMD, a G to T transversion at IVS6+3 was detected. This mutation resulted in skipping of exon 6 in the PLP mRNA of cultured fibroblasts. A patient who developed nystagmus at 16 months and progressive spastic ataxia at 18 months was found to have a 19-base pair (bp) deletion of a G-rich region near the 5' end of intron 3 of the PLP gene. A patient with a T to C transition at IVS3+2 and a patient with an A to G transition at IVS3+4 have the classic form of PMD. These, like the 19-bp deletion, are in intron 3, which is involved in PLP/DM20 alternative splice site selection.
Mutations in introns of the PLP gene, even at positions that are not 100% conserved at splice sites, are an important cause of PMD.
佩利措伊斯-梅茨巴赫病（PMD）是一种X连锁隐性中枢神经系统脱髓鞘疾病。大多数患者的蛋白脂蛋白（PLP）基因外显子存在重复或点突变。
描述5例PLP基因非编码区存在突变的PMD患者。
采用定量多重聚合酶链反应（PCR）和Southern印迹分析检测PLP基因重复，采用包括外显子-内含子边界的DNA序列分析检测PLP基因的突变。
排除PLP基因重复，在4个家族的5例PMD患者的非编码区鉴定到突变。在2例患有严重形式PMD的兄弟中，检测到IVS6+3处的G到T颠换。该突变导致培养的成纤维细胞的PLP mRNA中外显子6跳跃。一名在16个月时出现眼球震颤并在18个月时出现进行性痉挛性共济失调的患者被发现PLP基因内含子3的5'端附近富含G的区域有19个碱基对（bp）的缺失。一名在IVS3+2处有T到C转换的患者和一名在IVS3+4处有A到G转换的患者患有经典形式的PMD。这些突变，与19-bp缺失一样，位于内含子3中，该内含子参与PLP/DM20可变剪接位点的选择。
PLP基因内含子中的突变，即使在剪接位点并非100%保守的位置，也是PMD的重要病因。
