RNA腺苷脱氨酶(ADARs)能够催化RNA的腺嘌呤(A)脱氨基生成次黄嘌呤(I)，从而改变密码子编码和产生可变剪接，增加基因产物的多样性，对基因转录后调控起重要作用。DSH是常染色体显性遗传性色素异常性疾病，它的致病基因ADAR1是ADARs家族的重要成员，很可能与ADAR1突变引起的靶基因编辑异常有关，其确切发病机制仍不清楚。ADAR1的编码产物有p150和p110两种，其中p150是DSH发病的关键诱因。本课题将通过比较转录组序列和基因组序列，首先筛选出DSH患者皮肤组织内存在的异常编辑、异常剪接和差异表达基因，并进一步采用细胞学模型筛选出与p150有关且在DSH皮肤组织中存在异常的基因，作为进一步进行功能验证的候选基因。通过研究这些异常编辑对色素合成、分布和转运的影响，识别介导DSH的关键基因。该研究不仅有助于揭示色素代谢的调控机制，也可为研究RNA的转录后修饰提供很好的疾病模型。

The adenosine-to-inosine (A-to-I) RNA edited by ADARs is a post-transcriptional process that alters the RNA sequences by base modifications, thereby enhancing the diversity of gene products. Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant genodermatosis and caused by heterozygous mutation of ADAR1 gene, an important member of the ADARs family. Since the pathogenesis of DSH is not completely understood yet, we hypothesize that the deficiency of ADAR1 editing may be associated with the pigmentary disorders. ADAR1 gene is known to give rise to two protein isoforms (p150 and p110) that differ by N-terminal 295 amino acids, and the haploinsufficiency of the p150 isoform is the determinant of DSH. First, whole transcriptome data and whole genome sequence will be obtained from the skin tissues of DSH patients and controls. Several algorithms will be utilized to detect genes in editing/base substitution events,splicing and expression are different between the DSH patients and controls. Next，these aberrant genes associated with p150 isoform will be identified by using a keratinocyte melanocyte coculture model and will be used as the potential candidate genes responsible for DSH. Last, the functions of these candidate genes will be clarified on the transportation, distribution and synthesis of melanosomes, so as to identify the key genes involved in DSH. This project will provide useful information to investigate the underlying pathophysiological mechanisms of pigmentation disorders, and will set up a good model for studying ADARs in the future.