Elucidating Regulatory Mechanisms of Lamin B1 Expression in Autosomal Dominant Leukodystrophy

摘要 常染色体显性脑白质营养不良（ADLD）是一种致命的，成人发病，进行性神经系统疾病， 以广泛的中枢神经系统脱髓鞘为特征。大多数ADLD病例是由串联基因组 复制（ADLD-dup）涉及核纤层蛋白B1基因（LMNB 1），而一小部分是由基因组 LMNB 1上游缺失（ADLD-del）。这两种突变都被认为会导致CNS LMNB 1增加 表达并且是100%渗透剂即，所有携带突变基因的个体都会患病LMNB 1是一个 它是核纤层的组成部分，在维持核结构、调节基因表达、 表达和调节染色质定位。为什么一个广泛表达的基因的表达增加， 因为LMNB 1引起这种特定的脱髓鞘疾病是未知的。 结合患者数据，我们提出鼠和人源性少突胶质细胞（OL）谱系细胞 为了检验涉及导致ADLD的核纤层蛋白B1的基因组重排导致错误表达的假设， 核纤层蛋白B1基因我们将确定可能调节核纤层蛋白的调节元件和机制， 使用新型小鼠模型进行体外和体内B1表达。 我们提出的实验将使我们能够全面表征一种潜在的新型OL 调节元件，可以提供对ADLD的组织类型特异性的机制见解， OL功能和脱髓鞘疾病中的非编码调节元件。

Abstract Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult onset, progressive neurological disease that is characterized by widespread CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications (ADLD-dup) involving the lamin B1 gene (LMNB1) while a small subset is caused by genomic deletions upstream of LMNB1 (ADLD-del). Both these mutations are thought to cause increased CNS LMNB1 expression and are a 100% penetrant i.e., all individuals with the mutation develop the disease. LMNB1 is a component of the nuclear lamina and plays a critical role in maintaining nuclear architecture, regulating gene expression and modulating chromatin positioning. Why increased expression of a widely-expressed gene such as LMNB1 causes such a specific demyelination disorder is unknown. Using a combination of patient data, murine and human derived oligodendrocyte (OL) lineage cells we propose to test the hypothesis that genomic rearrangements involving Lamin B1 that cause ADLD result in mis-expression of the lamin B1 gene. We will identify regulatory elements and mechanisms that can potentially regulate Lamin B1 expression both in vitro and in vivo using a novel mouse model. The experiments we have proposed will allow us to comprehensively characterize a potentially novel OL regulatory element that can provide mechanistic insights into the tissue type specificity of ADLD and the role of non-coding regulatory elements in OL function and demyelinating diseases.