Elucidating Regulatory Mechanisms of Lamin B1 Expression in Autosomal Dominant Leukodystrophy

摘要 常染色体显性遗传性脑白质营养不良(ADLD)是一种致命的成人起病的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引起的 涉及Lamin B1基因(LMNB1)的重复(ADLD-DUP)，而一小部分是由基因组引起的 LMNB1上游的缺失(add-del)。这两种突变都被认为是导致CNS LMNB1增加的原因 并且是100%穿透性的，也就是说，所有带有突变的个体都会患上这种疾病。LMNB1是一种 核膜的组成部分，在维持核结构、调节基因 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 由于LMNB1导致这种特殊的脱髓鞘疾病，目前尚不清楚。 使用患者数据、小鼠和人类来源的少突胶质细胞(OL)谱系细胞的组合，我们提出 为了验证涉及Lamin B1的基因组重排导致ADLD导致错误表达的假设 层粘连蛋白B1基因。我们将确定可能调节LAM的调节要素和机制 使用一种新的小鼠模型在体外和体内表达B1。 我们提出的实验将使我们能够全面描述一种潜在的新颖的OL 调节元件，可以提供对ADLD组织类型特异性和ADLD的作用的机械性见解 OL功能中的非编码调控元件与脱髓鞘疾病。

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.