Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université de Strasbourg, Strasbourg, France; Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan; Department of Genetics, Research Institute of Environmental Medicine, Nagoya University, Nagoya, Japan.
Clinical Research Center for Diabetes, Tokushima University Hospital, Tokushima, Japan; Department of Interdisciplinary Researches for Medicine and Photonics, Institute of Post-LED Photonics, Tokushima, Japan.
J Dermatol Sci. 2020 Mar;97(3):201-207. doi: 10.1016/j.jdermsci.2020.01.012. Epub 2020 Jan 24.
Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterised by brittle hairs and various systemic symptoms, including photosensitivity and ichthyosis. While photosensitivity could result from DNA repair defects, other TTD clinical features might be due to deficiencies in certain molecular processes.
The aim of this study was to understand the pathophysiological mechanism of ichthyosis in TTD, focused on the transcriptional dysregulation.
TTD mouse skin tissue and keratinocytes were pathologically and physiologically examined to identify the alteration of lipid homeostasis in TTD with ichtyosis. Gene expression of certain lipid transporter was assessed in fibroblasts derived from TTD patients and TTD mouse keratinocytes.
Histopathology and electron microscopy revealed abnormal lipid composition in TTD mice skin. In addition to abnormal cholesterol dynamics, TTD mouse keratinocytes exhibit impaired expression of Liver X receptor (LXR) responsive genes, including Abca12, a key regulator of Harlequin ichthyosis, and Abcg1 that is involved in the cholesterol transport process in the epidermis. Strikingly, dysregulation of LXR responsive genes has been only observed in cells isolated from TTD patients who developed ichthyosis.
Our results suggest that the altered expression of the LXR-responsive genes contribute to the pathophysiology of ichthyosis in TTD. These findings provide a new drug discovery target for TTD.
先天性毛发硫营养不良症（TTD）是一种罕见的常染色体隐性遗传疾病，其特征为毛发脆弱和各种全身症状，包括光敏感和鱼鳞癣。虽然光敏感可能是由于 DNA 修复缺陷引起的，但 TTD 的其他临床特征可能是由于某些分子过程的缺陷所致。
本研究旨在了解 TTD 中鱼鳞癣的病理生理机制，重点关注转录失调。
对 TTD 小鼠皮肤组织和角质细胞进行病理和生理检查，以确定 TTD 合并鱼鳞病的脂质稳态改变。评估来自 TTD 患者和 TTD 小鼠角质细胞的成纤维细胞中某些脂质转运体的基因表达。
组织病理学和电子显微镜显示 TTD 小鼠皮肤的脂质组成异常。除了胆固醇动态异常外，TTD 小鼠角质细胞还表现出 LXR 反应基因表达受损，包括 Harlequin 鱼鳞病的关键调节因子 Abca12 和参与表皮胆固醇转运过程的 Abcg1。值得注意的是，仅在发生鱼鳞病的 TTD 患者分离的细胞中观察到 LXR 反应基因的失调。
我们的结果表明，LXR 反应基因的表达改变导致了 TTD 中鱼鳞癣的病理生理过程。这些发现为 TTD 的新药发现提供了一个新的靶点。
