Mutations in Myelin Protein Zero (MPZ) cause CMT1B, the second leading cause of CMT1. Many of the >200 mutations cause neuropathy through a toxic gain of function by the mutant protein such as ER retention, activation of the Unfolded Protein Response (UPR) or disruption of myelin compaction. While there is extensive literature on the loss of function consequences of MPZ in heterozygous Mpz +/− null mice, there is little known of the consequences of MPZ haploinsufficiency in humans. We identified six patients from different families with p.Tyr68Ter or p.Asp104fs heterozygous mutations of MPZ that are predicted to cause a premature termination and nonsense mediated decay of the mutant allele. Five patients were evaluated in Milan and one in Iowa City; all should be haploinsufficient for MPZ. Patients were evaluated clinically and by electrophysiology. Sensory ataxia dominated the clinical presentation with only mild weakness present in five of the six patients. Symptoms presented in adulthood in all patients and only one individual had a CMTNSv2 >5. Deep tendon reflexes were absent in all patients. Patients with likely MPZ loss of function due to mutations that cause haplodeficiency in MPZ have a mild, predominantly large fiber sensory neuropathy that serves as a human equivalent to the neuropathy observed in heterozygous Mpz null mice. Successful therapeutic approaches in treating Mpz deficient mice may be candidates for trials in these and similar patients.

中文翻译：

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功能丧失 MPZ 突变导致较轻的 CMT1B 神经病变

髓鞘蛋白零( MPZ ) 的突变导致 CMT1B，这是 CMT1 的第二大原因。超过 200 个突变中的许多突变通过突变蛋白的毒性获得功能（例如 ER 滞留、未折叠蛋白反应 (UPR) 的激活或髓鞘压实的破坏）引起神经病变。虽然有大量关于MPZ在杂合子 Mpz +/^ 空小鼠中丧失功能后果的文献，但对人类 MPZ 单倍体不足的后果知之甚少。我们确定了来自不同家族的 6 名患者，他们具有MPZ的 p.Tyr68Ter 或 p.Asp104fs 杂合突变预计会导致突变等位基因的过早终止和无意义介导的衰变。5 名患者在米兰接受评估，1 名在爱荷华市接受评估；对于 MPZ，所有都应该是单倍体不足的。对患者进行临床评估和电生理学评估。感觉共济失调在临床表现中占主导地位，六名患者中有五名仅存在轻度无力。所有患者均在成年期出现症状，只有一名患者的 CMTNSv2 >5。所有患者均无深腱反射。可能患有MPZ的患者由于导致 MPZ 单倍体缺陷的突变导致的功能丧失有一种轻微的、主要是大纤维感觉神经病变，它与在杂合 Mpz 缺失小鼠中观察到的神经病变类似。治疗 Mpz 缺陷小鼠的成功治疗方法可能是在这些和类似患者中进行试验的候选者。