Saporta Mario Andre, Katona Istvan, Zhang Xuebao, Roper Helen P, McClelland Louise, Macdonald Fiona, Brueton Louise, Blake Julian, Suter Ueli, Reilly Mary M, Shy Michael E, Li Jun
Department of Neurology, Wayne State University, Detroit, Michigan, USA.
Arch Neurol. 2011 Jun;68(6):814-21. doi: 10.1001/archneurol.2011.110.
Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations.
To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene.
The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice.
Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee.
A 7-year-old boy without the PMP22 gene.
Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers.
Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22.
外周髓鞘蛋白22（PMP22）单倍剂量不足会导致遗传性压力易感性周围神经病。然而，由于缺乏PMP22基因完全缺失的患者，PMP22蛋白在人类中的生物学功能在很大程度上尚未得到探索。
通过研究一名无PMP22基因的男孩和无Pmp22基因的小鼠，探讨PMP22在外周神经系统中的功能。
将一名PMP22纯合缺失患者的临床和病理特征与Pmp22基因敲除小鼠的特征进行比较。
在英国的三级医院进行临床评估。在西米德兰兹地区遗传学实验室进行分子诊断。在密歇根州底特律的韦恩州立大学进行免疫组织化学和电子显微镜分析。在田纳西州纳什维尔的范德比尔特大学对Pmp22+/-和基因敲除小鼠进行分析。
一名7岁无PMP22基因的男孩。
先证者的运动和感觉障碍不呈长度依赖性。在颅部肌肉中发现无力，但四肢未受累。大纤维感觉模式严重异常，在髓鞘成熟之前就已出现。这与胚胎发育期间PMP22主要在颅运动神经元和背根神经节中表达的时间模式一致，在成年期则无法检测到。此外，有明显的髓鞘形成雪旺细胞成熟缺陷；这些缺陷在运动神经纤维中比在感觉神经纤维中更显著。
综上所述，数据表明PMP22对于早期发育过程中表达PMP22的神经元（如颅运动神经元和脊髓感觉神经元）的正常功能很重要。此外，PMP22缺乏对运动和感觉神经髓鞘形成的影响不同，这可能导致了PMP22缺失患者独特的临床表型。
