A harlequin ichthyosis pig model with a novel ABCA12 mutation can be rescued by acitretin treatment  

作　　者：Xiao Wang Chunwei Cao Yongshun Li Tang Hai Qitao Jia Ying Zhang Qiantao Zheng Jing Yao Guosong Qin Hongyong Zhang Ruigao Song Yanfang Wang Guanghou Shui Sin Man Lam Zhonghua Liu Hong Wei Anming Meng Qi Zhou Jianguo Zhao 

机构地区：[1]State Key Laboratory of Stem Cell and Reproductive Biology,Institute of Zoology,Chinese Academy of Sciences,Beijing 100101,China [2]University of Chinese Academy of Sciences,Beijing 100049,China [3]State Key Laboratory of Animal Nutrition,Institute of Animal Science,Chinese Academy of Agricultural Sciences,Beijing 100081,China [4]State Key Laboratory of Molecular Developmental Biology,Institute of Genetics and Developmental Biology,Chinese Academy of Sciences,Beijing 100101,China [5]College of Life Science,Northeast Agricultural University of China,Harbin 150030,China [6]Department of Laboratory Animal Science,College of Basic Medical Sciences,Third Military Medical University,Chongqing 400038,China [7]School of Life Sciences,Tsinghua University,Beijing 100084,China [8]Chinese Swine Mutagenesis Consortium,Beijing 100101,China

出　　处：《Journal of Molecular Cell Biology》2019年第12期1029-1041,共13页分子细胞生物学报（英文版）

基　　金：the Strategic Priority Research Programs of CAS(XDA16030300);the National Natural Science Foundation of China(81671274,31272440,and 31801031);the National Transgenic Project of China(2016ZX08009003-006-007);the Elite Youth Program of the Chinese Academy of Agricultural Sciences(ASTIP-IAS05).

摘　　要：Harlequin ichthyosis (HI) is a severe genetic skin disorder and caused by mutation in the ATP-binding cassette A12 (ABCA12) gene. The retinoid administration has dramatically improved long-term survival of HI, but improvements are still needed. However, the ABCA12 null mice failed to respond to retinoid treatment, which impedes the development of novel cure strategies for HI. Here we generated an ethylnitrosourea mutagenic HI pig model (named Z9), which carries a novel deep intronic mutation IVS49-727 A>G in the ABCA12 gene, resulting in abnormal mRNA splicing and truncated protein production. Z9 pigs exhibit significant clinical symptom as human patients with HI. Most importantly, systemic retinoid treatment significantly prolonged the life span of the mutant pigs via improving epidermal maturation, decreasing epidermal apoptosis, and triggering the expression of ABCA6. Taken together, this pig model perfectly resembles the clinical symptom and molecular pathology of patients with HI and will be useful for understanding mechanistic insight and developing therapeutic strategies.

关 键 词：harlequin ichthyosis ABCA12 pig model ACITRETIN ENU mutagenesis deep intronic mutation 

分 类 号：R37[医药卫生—病原生物学]