PDF(Pubmed)
Abstract：
Demyelinating Charcot-Marie-Tooth 4G (CMT4G) results from a recessive mutation in the 5\'UTR region of the Hexokinase 1 (HK1) gene. HK participates in mitochondrial calcium homeostasis by binding to the Voltage-Dependent Anion Channel (VDAC), through its N-terminal porin-binding domain. Our hypothesis is that CMT4G mutation results in a broken interaction between mutant HK1 and VDAC, disturbing mitochondrial calcium homeostasis. We studied a cohort of 25 CMT4G patients recruited in the French gypsy population. The disease was characterized by a childhood onset, an intermediate demyelinating pattern, and a significant phenotype leading to becoming wheelchair-bound by the fifth decade of life. Co-IP and PLA studies indicated a strong decreased interaction between VDAC and HK1 in the patients\' PBMCs and sural nerve. We observed that either wild-type HK1 expression or a peptide comprising the 15 aa of the N-terminal wild-type HK1 administration decreased mitochondrial calcium release in HEK293 cells. However, mutated CMT4G HK1 or the 15 aa of the mutated HK1 was unable to block mitochondrial calcium release. Taken together, these data show that the CMT4G-induced modification of the HK1 N-terminus disrupts HK1-VDAC interaction. This alters mitochondrial calcium buffering that has been shown to be critical for myelin sheath maintenance.
摘要：
脱髓鞘Charcot-Marie-Tooth4G(CMT4G)由己糖激酶1(HK1)基因5UTR区的隐性突变引起。HK通过与电压依赖性阴离子通道（VDAC）结合参与线粒体钙稳态，通过其N端孔蛋白结合结构域。我们的假设是CMT4G突变导致突变HK1和VDAC之间的相互作用中断，干扰线粒体钙稳态。我们研究了在法国吉普赛人群中招募的25名CMT4G患者。这种疾病的特点是儿童期发病，中间脱髓鞘模式，和一个重要的表型，导致在生命的第五个十年成为轮椅约束。Co-IP和PLA研究表明，患者PBMC和腓肠神经中VDAC和HK1之间的相互作用强烈降低。我们观察到野生型HK1表达或包含N末端野生型HK1施用的15个氨基酸的肽降低了HEK293细胞中的线粒体钙释放。然而,突变的CMT4GHK1或突变的HK1的15个氨基酸无法阻断线粒体钙的释放。一起来看,这些数据表明，CMT4G诱导的HK1N末端修饰破坏了HK1-VDAC相互作用。这改变了线粒体钙缓冲，这已被证明对髓鞘的维持至关重要。
