第一部分 PMD的临床遗传学特点分析
目的：通过对佩梅病 （Pelizaeus–Merzbacher disease, PMD）患者进行临床遗传学特点分析以及随访，了解疾病自然史及转归，阐明基因型与表型关系，为PMD的精确诊疗、预后评估及产前诊断打下基础。
方法：从2005年以来就诊于北京大学第一医院诊断为PMD的患者中纳入研究对象。采用问卷或电话、微信的方式对患者进行随访。采集PMD患者临床资料，分析其自然病史及临床进展。应用多重连接探针扩增 （multiplex ligation probe amplification, MLPA）和Sanger或全外显子测序 （whole-exome sequencing, WES）进行遗传学分析。根据基因诊断结果分析自然史和基因型-表型相关性。
结果：本中心共诊断141例患者，随访研究共纳入111位患者。包括105例男性和6例女性患者，12.6%的患者有家族史，首次就诊和最后一次随访的中位年龄分别为12个月（1，336）和78个月（7，482）。4例患者为分别来自于两个家庭的兄弟，6例患者在最后一次随访中已去世。
在所有患者中，发育迟缓是最常见（100%）的主诉，眼震和肌张力低下是PMD患者中最常见的首发症状。截止最后一次随访，共计78.4％的患者可以竖头，72.1％的患者可以说单词。很少有患者可以独自站立（9.0％）或走路（4.5％）。超过一半的患者（58.2%）眼震症状得到改善，肌张力低下的患者可能在后期出现肌张力障碍及退化，例如关节挛缩，痉挛性截瘫及共济失调等。7.2%的患者出现癫痫发作，1例患者在7岁时因癫痫发作去世。与中间型和经典型相比，先天型的患者发病较早，运动和认知能力获得的年龄较晚（p<0.05），临床转归例如出现脑干功能不全或肌张力障碍的占比更高。
141例患者中检出110例（78.0%）PLP1重复突变，31例（22.0%）PLP1点突变，其中12例为新生突变，26种突变已被报道。突变F32L在3例患者中被检出，P126S突变以往在2例患者中被报道。31例点突变中29例为错义突变，2例缺失突变。2例 （G208D, G208V）错义突变发生在同一位点上。更多的PLP1点突变患者临床上表现为先天型，而PLP1重复患者则更多地被归为中间型（p<0.001）。随访中38个患者家系共计进行54次产前诊断，PLP1检测结果提示：17例胎儿基因型与先证者相同，16例携带先证者的致病突变，21例胎儿为野生型。
结论：PMD患者最常见的起病症状为眼震或肌张力低下，随后出现智力运动发育落后、肌张力障碍伴或不伴癫痫共济失调等。PLP1点突变多表现为先天型，而PLP1重复的患者多表现为中间型。相对于中间型和经典型，先天型患者起病早，获得的智力运动发育里程碑更少，获得年龄更晚，临床转归更差。产前诊断为避免患儿家庭再次生育同样的患者提供了有效的帮助。

第二部分 PLP1突变导致PMD的细胞学机制研究
目的：通过PLP1突变对细胞器互作网络稳态的影响，揭示PLP1突变致病的细胞分子学机制，为PMD的临床药物筛选提供实验基础。
方法：应用超高分辨率结构光成像显微镜（spinning-disc pinhole-based structured illumination microscopy, SD-SIM）检测PLP1点突变中PLP1在Mo3.13细胞内的运输途径及PLP1重复突变患者皮肤成纤维细胞内质网 （endoplasmic reticulum, ER）和线粒体之间的相互作用，利用Seahorse XF细胞外分析仪实时监测线粒体呼吸功能。
结果： PLP1点突变主要影响PLP1在膜上的表达从而发挥致病作用，不同PLP1点突变可表现为不同严重程度的细胞表型：最严重的表型为Mo3.13细胞中细胞膜上的“丝状伪足样”结构消失，大量的PLP1潴留在内质网中；其次为Mo3.13细胞“丝状伪足”结构部分存在，大部分蛋白质出现在囊泡（溶酶体）结构中；最轻的表型为Mo3.13细胞质膜上的“丝状伪足”结构存在且有PLP1的表达，部分未转运到细胞膜上的蛋白质出现在囊泡（溶酶体）结构中。而细胞表型的轻重程度与相应突变体在患者中表现出临床表现的轻重相一致。胆固醇的补充能够且仅能改善最严重的细胞表型。
    在PLP1重复突变患者的皮肤成纤维细胞中，相对于对照组，PLP1的表达量升高（p=0.037）；更多的内质网形态发生改变：表现为外周ER“片状”结构在细胞内的占比增大（p<0.001），形态变大（p<0.001）。异形内质网周围区域与线粒体的接触面增多，距离变近（p<0.001）。与此同时，线粒体的形态也发生改变，患者皮肤成纤维细胞中线粒体长度比对照组短，“管状”线粒体占比减少，“膨大点状”（Large Spherical Mitochondria, LASMs）等异形线粒体的占比增多（p<0.05）。对线粒体呼吸功能的检测显示PLP1重复突变患者皮肤成纤维细胞最大呼吸强度较对照组低 （p<0.001）。但患者组间不同内质网，线粒体形态的占比及线粒体呼吸强度没有显著差异（p>0.05）。
结论：PLP1点突变可改变PLP1在细胞内的运输及在膜上表达的结果，产生与患者表型轻重程度一致的细胞表型，胆固醇可改善最严重的细胞表型。PLP1重复突变可导致连接线粒体和ER的线粒体相关膜结构 （Mitochondria-associated Membranes, MAMs）的距离减小，从而产生致病作用。
 

Part I: Genotype-phenotype correlation analyses of Pelizaeus–Merzbacher disease

Background: To investigate the natural history and genotype-phenotype correlation of Pelizaeus–Merzbacher disease (PMD) in a cohort study and lay a foundation of precise diagnosis and treatment as well as genetic counseling.
Method: Patients who met the criteria for PMD were enrolled in our study. Patients were followed up 1-3 times and interviewed via questionnaire survey, telephone or WeChat. Clinical data were collected to analyze the natural history and clinical progress of PMD patients. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Differences in natural history and genotype- phenotype correlations were analyzed.
Result: 141 patients were diagnosis in our center, 111 patients were enrolled in our follow-up study, including 105 males and 6 females. 12.6% of the patients have more than one affected families. The median age at first visit and the last follow-up were 12 months (1, 336) and 78 months (7, 482), respectively. Four patients were bothers from two families, six patients have died in our last follow-up.
Developmental delay was the most common complaint in all of the children, nystagmus and hypotonia were the most common initial symptoms observed in the PMD patients. A total of 78.4% of the patients could control their head and 72.1% of the patients could speak words. Few patients could stand (9.0%) or walk (4.5%) by themselves. More than half of the patients’ nystagmus conditions improved and patients with hypotonia can deteriorate to dystonia. For example joint contracture, spasticity tetraparesis, ataxia and so on. 7.2% of the patients had seizures in the follow-up study and one patient even died of seizures in his 7 years old. More PLP1 point mutations patients were categorized into the connatal group, while the patients with PLP1 duplications were categorized into the transitional group (p<0.001). Patients in the connatal group had an earlier disease onset and acquired motor and recognized skills at a later age than the patients in the transitional and classic groups (p<0.05).
110 patients were diagnosed with PLP1 duplication mutation while PLP1 point mutation were found in 31 patients, among which 12 mutations were De novo. The mutation of F32L was detacted in three patients in our cohort, P126S has been reported in two patients previously. 29 out of 31 mutations were missence mutations while the other 2 mutations were deletion mutations. Two of the missence mutations were different mutations occurring at the same position. A total of 54 prenatal diagnoses were made in 38 patient families during the follow-up. PLP1 genetic test results indicated that 17 fetuses had the same genotype as the proband, 16 fetuses carried pathogenic mutations of the proband, and 21 fetuses were wild type.
Conclusion: The PMD patients had an early disease onset with nystagmus and hypotonia followed by development delay, hypotonia deterioration with/without seizures and ataxia. Patients who identified with PLP1 duplication were more categorized into the transitional group, while more patients with point mutations were categorized into the connatal group. Compared with transitional and classical group, patients with connatal group has a more earlier disease onset, lower level of development and worse clinical outcome. Prenatal diagnosis provides effective help to prevent the probands’ families from giving birth to a same patient.

Part II: Potential pathogenicity resulted from PLP1 mutations in patients with Pelizaeus–Merzbacher disease

Objective: This study aim to analyze the influence of PLP1 mutations on the organelle interaction network(OIN), which imply the cellular mechanism of PLP1 mutation and also lay a foundation for drug screening of PMD.
Method: With spinning-disc pinhole-based structured illumination microscopy (SD-SIM), we followed up with PLP1 expression in Mo3.13 and examined the interactions between endoplasmic reticulum (ER) and mitochondria in patients’ fibroblasts of PLP1 duplication. we measured mitochondrial respiration with a Seahorse XF Extracellular Analyzer.
Result: Different pathogenicities were found between PLP1 point mutation and PLP1 duplication. PLP1 point mutation affected the PLP1 delivering to the plasma membrane. while different mutants lead to either abnormal retention of PLP1 in endoplasmic reticulum (ER) without any filopodia in the membrane, or its mis-targeting to vesicular structures (lysosomes) with some filopodia, or trafficking and exocytosis of PLP1-containing vesicles and with PLP1 targetting to the filipodia in the memrane, which from the most severe type to the mildest type. These cellular phenotypes correlate nicely with the severity of disease phenotype in patients. Cholesterol only could alter the most severe cellular phenotypes.
In the PLP1 duplication patients’ fibroblasts, compared with control’s fibroblasts, PLP1 expressions in the patients’ fibroblasts are higher, more “expanded ER-sheets” were seen in the peripherial ER(p<0.001). Meanwhile, more shorter and less “Tubular” mitochondria and more “Large Spherical Mitochondria (LASMs)” were found in PLP1 duplication patients’ fibroblasts(p<0.05). Moreover, the maximal oxygen consumption rate (OCR) were lower in patients’ group compared with control (p<0.001), but there were no significant difference between patients’ group of the above results.
Conclusion: PLP1 point mutation can affect the PLP1 delivering to the plasma membrane, with the most severe type was abnormal retention of PLP1 in endoplasmic reticulum (ER) and the mildest type was PLP1 targetting to the filipodia in the membranes. Cholesterol only could alter the most severe cellular phenotypes.While in PLP1 duplication patients, the mitochondria dysfunction can due to the larger interfaces between ER and mitochondria. which can partly explain the pathogenicity mechanism of PLP1 duplication.

 

摘要 I
ABSTRACT IV
目录 VIII
主要符号对照表 XI
第一章 文献综述 佩梅病临床遗传学特点分析及PLP1致病的细胞学机制研究 1
1.1 PMD概述 1
1.1.1 PMD的命名及流行病学特点 1
1.1.2 PMD的病理学特点 1
1.2 PMD临床特点研究进展 2
1.2.1 PMD临床表现 2
1.2.2 PMD诊断标准及分型 2
1.3 PMD的遗传学特点 4
1.3.1 致病基因PLP1及蛋白脂蛋白I型 4
1.3.2 PLP1突变类型 5
1.4 PMD的基因型表型关系 5
1.5 PLP1突变致病的细胞学机制研究 7
1.5.1 PLP1与髓鞘 7
1.5.2 PLP1突变影响髓鞘结构及功能的作用机制 9
1.6 PMD的治疗及预后 14
1.7 小结 14
第二章 PMD临床遗传学特点分析 16
2.1 引言 16
2.2 研究目的 17
2.3 研究对象及方法 17
2.3.1 研究对象 17
2.3.2 临床研究方法 18
2.3.3 临床随访研究 19
2.3.4 遗传学分析方法 20
2.3.5 伦理及知情同意 22
2.3.6 统计学分析 22
2.4 结果 23
2.4.1 患者一般信息特点 23
2.4.2 PMD患者的临床特点 23
2.4.3 PMD患者的遗传学特点 27
2.4.5 PMD患者基因型-表型之间的关系 31
2.5 讨论 43
2.5.1 PMD临床特点结果讨论 43
2.5.2 PMD遗传特点结果讨论 43
2.5.3 PMD基因型与表型的关系讨论 44
2.5.4 PMD的预后讨论 45
2.6 局限性 45
2.7 小结 45
第三章 PLP1突变致病的细胞学机制研究 47
3.1 引言 47
3.2 研究目的 47
3.3 材料和方法 48
3.3.1 研究对象 48
3.3.2 实验材料及仪器 48
3.3.3 研究方法 50
3.4 结果 60
3.4.1 入组患者的临床及遗传学特点 60
3.4.2 PLP1点突变细胞学研究结果 62
3.4.3 PLP1重复突变细胞学研究结果 64
3.5 讨论 70
3.5.1 PLP1点突变细胞学致病机制的讨论 70
3.5.2 PLP1重复突变细胞学致病机制的讨论 71
3.5.3 PLP1突变与细胞表型关系的讨论 74
3.5.4 胆固醇纠正细胞表型的临床意义 75
3.6 局限性 75
3.7 小结 76
第四章 结论及展望 77
4.1 PMD临床遗传学特点 77
4.2 PLP1突变致病的细胞学机制 77
参考文献 78
附录A 佩梅病（PMD）随访问卷 91
附录B 本中心PMD患者产前诊断结果汇总 112
附录C 三种PLP1重复突变患者和对照组皮肤成纤维细胞光成像 114
致谢 115
北京大学学位论文原创性声明和使用授权说明 116

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