Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer
Mutations in lipid transporter ABCA12 in harlequin ichthyosis and functional recovery by corrective gene transfer
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DOI：
10.1172/jci24834
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发表时间：
2005-07-01
影响因子：
15.9
通讯作者：
Shimizu, H
中科院分区：
文献类型：
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作者：
Akiyama, M;Sugiyama-Nakagiri, Y;Shimizu, H
丑角鱼鳞病（HI）是一种毁灭性的皮肤疾病，其根本原因不明。异常的角质形成细胞板层颗粒（LGs）是HI皮肤的标志。ABCA 12是ATP结合盒转运蛋白家族的成员，已知ABCA亚家族的成员具有与脂质转运蛋白密切相关的功能。ABCA 3通过来自肺泡11型细胞的LG参与脂质分泌，并且已报道ABCA 12中的错义突变引起板层状鱼鳞病2型，一种较温和形式的鱼鳞病。因此，我们假设HI可能是由导致严重ABCA12缺陷的突变引起的。我们确定了5个不同的ABCA12突变，无论是在复合杂合或纯合状态，在4个HI家庭的患者。所有突变导致ABCA12高度保守区域的截短或缺失。免疫电镜显示ABCA12定位于正常表皮角质形成细胞的LGs。我们证实，ABCA12缺陷导致充血的脂质分泌在培养的HI角质形成细胞，并成功地获得纠正基因转移ABCA12后的LG脂质分泌的恢复。我们得出结论，ABCA12作为表皮角质形成细胞脂质转运蛋白发挥作用，ABCA12缺陷导致皮肤脂质屏障丧失，导致HI。我们的研究结果不仅允许基于DNA的早期产前诊断，但也表明基因治疗HI的可能性。
Harlequin ichthyosis (HI) is a devastating skin disorder with an unknown underlying cause. Abnormal keratinocyte lamellar granules (LGs) are a hallmark of HI skin. ABCA12 is a member of the ATP-binding cassette transporter family, and members of the ABCA subfamily are known to have closely related functions as lipid transporters. ABCA3 is involved in lipid secretion via LGs from alveolar type 11 cells, and missense mutations in ABCA12 have been reported to cause lamellar ichthyosis type 2, a milder form of ichthyosis. Therefore, we hypothesized that HI might be caused by mutations that lead to serious ABCA12 defects. We identify 5 distinct ABCA12 mutations, either in a compound heterozygous or homozygous state, in patients from 4 HI families. All the mutations resulted in truncation or deletion of highly conserved regions of ABCA12. Immunoelectron microscopy revealed that ABCA12 localized to LGs in normal epidermal keratinocytes. We confirmed that ABCA12 defects cause congested lipid secretion in cultured HI keratinocytes and succeeded in obtaining the recovery of LG lipid secretion after corrective gene transfer of ABCA12. We concluded that ABCA12 works as an epidermal keratinocyte lipid transporter and that defective ABCA12 results in a loss of the skin lipid barrier, leading to HI. Our findings not only allow DNA-based early prenatal diagnosis but also suggest the possibility of gene therapy for HI.