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.

中文翻译：

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阿维A治疗可以挽救具有新的ABCA12突变的丑角鱼鳞鱼模型。

丑角鱼鳞病（HI）是一种严重的遗传性皮肤病，由ATP结合盒A12（ABCA12）基因突变引起。类维生素A给药显着改善了HI的长期存活率，但仍需要改进。但是，ABCA12无效小鼠对类维生素A治疗无效，这阻碍了HI新型治疗策略的发展。在这里，我们生成了乙基亚硝基脲诱变的HI猪模型（命名为Z9），该模型在ABCA12基因中带有新型的深度内含子突变IVS49-727 A> G，从而导致异常的mRNA剪接和截短的蛋白质产生。Z9猪表现出与人类HI患者一样的明显临床症状。最重要的是，通过改善表皮成熟度，减少表皮细胞凋亡，全身性类维生素A处理可显着延长突变猪的寿命，并触发ABCA6的表达。综上所述，这种猪模型完全类似于HI病人的临床症状和分子病理学，将有助于理解机械学见解和制定治疗策略。