Impaired production of skin barrier lipid acylceramides and abnormal localization of PNPLA1 due to ichthyosis-causing mutations in PNPLA1
Impaired production of skin barrier lipid acylceramides and abnormal localization of PNPLA1 due to ichthyosis-causing mutations in PNPLA1
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DOI：
10.1016/j.jdermsci.2022.07.008
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发表时间：
2022-08-01
影响因子：
4.6
通讯作者：
Kihara, Akio
中科院分区：
文献类型：
--
作者：
Nohara, Tomohiro;Ohno, Yusuke;Kihara, Akio
背景：PNPLA1是常染色体隐性遗传先天性鱼鳞病的致病基因。转酰基酶 PNPLA1 通过催化亚油酸从甘油三酯转移到 omega-羟基神经酰胺，产生 ε-O-酰基神经酰胺（酰基神经酰胺），这是皮肤屏障功能所必需的脂质。 目的：我们旨在验证在鱼鳞病患者中发现的 PNPLA1 突变参与发病机制，并阐明这些突变对酰基神经酰胺生成的影响之间的相关性。方法：使用基于细胞的测定系统研究PNPLA1突变体的酰基神经酰胺产生活性，其中野生型PNPLA1或每个PNPLA1突变体与参与酰基神经酰胺合成的酶共过表达。通过间接免疫荧光显微镜检查每个突变对PNPLA1的ABHD5依赖性脂滴定位的影响。结果：在16个PNPLA1错义突变中，除C216R突变外，15个突变导致酰基神经酰胺产生活性完全丧失，而C216R突变对该活性影响微弱。无活性的突变体的细胞内定位因突变体而异。两个突变体（S19L和D172N）定位于脂滴，八个突变体（S53L、S53W、A59V、T125N、D129E、R166C、P234S和P235L）部分定位于其中。五个突变体（A34P、A34T、S53P、K141E 和 P163L）分布在整个细胞质中。结论：本研究中检查的 PNPLA1 错义突变与鱼鳞病病理有关。 C216R 突变对酰基神经酰胺产生活性的微弱影响与鱼鳞病患者的轻微症状相关。 16 个 PNPLA1 突变体根据其酰基神经酰胺产生活性和定位被分为四组。 (C) 2022 年日本皮肤病研究学会。由 Elsevier B.V. 出版。保留所有权利。
Background: PNPLA1 is a causative gene of autosomal recessive congenital ichthyosis. The transacylase PNPLA1 produces epsilon-O-acylceramides (acylceramides), lipids essential for the skin barrier function, by catalyzing the transfer of a linoleic acid from triglycerides to omega-hydroxyceramides.Objective: We aimed to validate the involvement of PNPLA1 mutations found in ichthyosis patients in the pathogenesis and elucidate the correlation between the effects of these mutations on acylceramide-pro-ducing activity and ichthyosis pathology.Methods: Acylceramide-producing activity of PNPLA1 mutants was investigated using a cell-based assay system, in which wild-type PNPLA1 or each PNPLA1 mutant was co-overexpressed with the enzymes involved in acylceramide synthesis. The effect of each mutation on the ABHD5-dependent lipid droplet localization of PNPLA1 was examined through indirect immunofluorescence microscopy.Results: Of 16 PNPLA1 missense mutations, 15 mutations, except the C216R mutation, resulted in a complete loss of acylceramide-producing activity, while the C216R mutation weakly affected this activity. Intracellular localization of mutants with no activity varied among mutants. Two mutants (S19L and D172N) localized in lipid droplets, and eight mutants (S53L, S53W, A59V, T125N, D129E, R166C, P234S, and P235L) partially localized there. Five mutants (A34P, A34T, S53P, K141E, and P163L) localized throughout the cytosol.Conclusion: The PNPLA1 missense mutations examined in this study are responsible for ichthyosis pathology. The weak effect of C216R mutation on acylceramide-producing activity correlates with the mild symptoms of the ichthyosis patient. Sixteen PNPLA1 mutants were classified into four groups based on their acylceramide-producing activity and localization. (C) 2022 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.