Centre for Cutaneous Research, Blizard Institute, Barts & The London School of Medicine and Dentistry, Queen Mary, University of London, London, E1 2AT, UK.
Cell Tissue Res. 2013 Feb;351(2):281-8. doi: 10.1007/s00441-012-1474-9. Epub 2012 Aug 4.
Harlequin ichthyosis (HI) is a devastating autosomal recessive congenital skin disease. It has been vital to elucidate the biological importance of the protein ABCA12 in skin-barrier permeability, following the discovery that ABCA12 gene mutations can result in this rare disease. ATP-binding cassette transporter A12 (ABCA12) is a member of the subfamily of ATP-binding cassette transporters and functions to transport lipid glucosylceramides (GlcCer) to the extracellular space through lamellar granules (LGs). GlcCer are hydrolysed into hydroxyceramides extracellularly and constitute a portion of the extracellular lamellar membrane, lipid envelope and lamellar granules. In HI skin, loss of function of ABCA12 due to null mutations results in impaired lipid lamellar membrane formation in the cornified layer, leading to defective permeability of the skin barrier. In addition, abnormal lamellar granule formation (distorted shape, reduced in number or absent) could further cause aberrant production of LG-associated desquamation enzymes, which are likely to contribute to the impaired skin barrier in HI. This article reviews current opinions on the patho-mechanisms of ABCA12 action in HI and potential therapeutic interventions based on targeted molecular therapy and gene therapy strategies.
遗传性鱼鳞病（HI）是一种破坏性的常染色体隐性先天性皮肤疾病。在发现 ABCA12 基因突变可导致这种罕见疾病后，阐明 ABCA12 蛋白在皮肤屏障通透性方面的生物学重要性至关重要。三磷酸腺苷结合盒转运蛋白 A12（ABCA12）是三磷酸腺苷结合盒转运蛋白亚家族的成员，其功能是通过板层小体（LG）将脂质葡萄糖神经酰胺（GlcCer）转运到细胞外空间。GlcCer 在细胞外水解为羟基神经酰胺，构成细胞外板层膜、脂质包膜和板层小体的一部分。在 HI 皮肤中，由于无效突变导致 ABCA12 功能丧失，会导致细胞层中脂质板层膜形成受损，从而导致皮肤屏障通透性缺陷。此外，板层小体形成异常（形状扭曲、数量减少或缺失）可能会进一步导致 LG 相关脱屑酶的异常产生，这可能有助于 HI 中受损的皮肤屏障。本文综述了 ABCA12 在 HI 中的作用的病理机制的现有观点，以及基于靶向分子治疗和基因治疗策略的潜在治疗干预措施。
