Sabet A, Li J, Ghandour K, Pu Q, Wu X, Kamholz J, Shy M E, Cambi F
Department of Neurology, University of Kentucky, Lexington, KY 40536, USA.
Neurology. 2006 Oct 10;67(7):1141-6. doi: 10.1212/01.wnl.0000238499.37764.b1.
To demonstrate that intronic mutations in the myelin protein zero (MPZ) cause Charcot-Marie-Tooth neuropathy 1B (CMT1B) by disrupting MPZ splicing.
We report a family with a T>G transversion at the invariant + 2 position in intron 4 of MPZ (c.614 + 2T>G) that abolishes 5' donor site recognition and is predicted to alter MPZ splicing. We obtained detailed clinical and neurophysiologic analysis of the family. We performed skin biopsies to investigate splicing abnormalities, MPZ protein levels, and localization in myelinated nerves.
Patients developed a late onset neuropathy with minimally slow nerve conduction velocities. Skin biopsies confirmed the predicted skipping of exon 4 and downstream frameshift of the mutant MPZ. Quantitative immuno-EM demonstrated normal nerve MPZ levels, suggesting that the mutant MPZ was transported to compact myelin.
Intronic mutations cause CMT1B by disrupting splicing and certain MPZ mutations may cause neuropathy by interacting with the wild type MPZ in the extracellular space of compact myelin.
证明髓鞘蛋白零（MPZ）基因内含子突变通过破坏MPZ剪接导致遗传性运动感觉神经病1B型（CMT1B）。
我们报告了一个家系，其MPZ基因第4内含子的不变+2位置发生了T>G颠换（c.614+2T>G），该突变消除了5'供体位点识别，并预计会改变MPZ剪接。我们对该家系进行了详细的临床和神经生理学分析。我们进行了皮肤活检，以研究剪接异常、MPZ蛋白水平以及在有髓神经中的定位。
患者出现迟发性神经病，神经传导速度轻度减慢。皮肤活检证实了预测的第4外显子跳跃和突变型MPZ的下游移码。定量免疫电镜显示神经MPZ水平正常，表明突变型MPZ被转运至致密髓鞘。
内含子突变通过破坏剪接导致CMT1B，某些MPZ突变可能通过在致密髓鞘细胞外空间与野生型MPZ相互作用而导致神经病。
