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.