Arai Ayami, Takeichi Takuya, Wakamoto Hiroyuki, Sassa Takayuki, Ito Yasutoshi, Murase Yuya, Ogi Tomoo, Akiyama Masashi, Kihara Akio
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
J Dermatol Sci. 2022 Sep;107(3):114-122. doi: 10.1016/j.jdermsci.2022.08.003. Epub 2022 Aug 9.
Sjögren-Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation.
To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS.
Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry.
A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes.
These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.
舍格伦 - 拉尔松综合征（SLS）是一种神经皮肤疾病，其致病基因是脂肪醛脱氢酶ALDH3A2，鱼鳞病是其主要皮肤症状。角质层含有多种神经酰胺，其中ω - O - 酰基神经酰胺（酰基神经酰胺）和蛋白质结合神经酰胺对于皮肤渗透屏障的形成至关重要。
确定导致SLS发病机制的神经酰胺类别/种类以及在SLS中受损的酶。
从一名SLS患者及其父母的外周血样本中收集基因组DNA，并进行全基因组测序和桑格测序。从SLS患者和健康志愿者的角质层样本中提取脂质，并通过液相色谱 - 串联质谱法进行神经酰胺谱分析。
在患者的ALDH3A2基因中发现了一个重复（c.55_130dup）和一个错义突变（p.Lys447Glu）。患者所有酰基神经酰胺类别的水平均降低，总酰基神经酰胺水平为健康对照的25％。还观察到几种非酰化神经酰胺的减少：长链碱基部分含有植物鞘氨醇或6 - 羟基鞘氨醇的神经酰胺分别降至对照水平的24％和41％，以α - 羟基脂肪酸为脂肪酸部分的神经酰胺降至29％。许多非酰化神经酰胺类别的脂肪酸部分缩短。
这些结果表明，酰基神经酰胺水平降低是SLS鱼鳞病症状的主要原因，但其他神经酰胺类别的减少也可能有关。
