Department of Genetics, Gunma Children's Medical Center, Shibukawa, Japan.
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
Congenit Anom (Kyoto). 2025 Jan-Dec;65(1):e12587. doi: 10.1111/cga.12587.
Sjögren-Larsson syndrome (SLS) is an autosomal recessive leukodystrophy characterized by ichthyosis, intellectual disability, and progressive spastic paralysis caused by biallelic pathogenic variants in the ALDH3A2 gene that encodes the fatty aldehyde dehydrogenase, fatty aldehyde dehydrogenase (FALDH); FALDH catalyzes several metabolic reactions involved in fatty aldehyde oxidation. Only a few studies have been performed to determine the lipid profile of patients with SLS. In a previous postmortem study of the brain of a 65-year-old patient with SLS, lipidomic analysis revealed an accumulation of long-chain unsaturated ether lipid species in the white matter and gray matter. In the present study, we established a disease model using patient-derived neuronal and oligodendrocyte lineage cells to analyze the lipid metabolism and gene expression profiles in SLS. To achieve this, we generated induced pluripotent stem cells (iPSCs) from two patients with the SLS phenotype carrying previously known ALDH3A2 pathogenic variants: One was a compound heterozygote (c.1339A>G:p.(Lys447Glu) and c.57_132dup:p.(Ile45Serfs*34)) and the other was a homozygote (c.1339A>G: p.(Lys447Glu)). The FALDH activity was almost zero in the SLS-iPSC lines established from both patients. Phospholipid analysis of neurospheres, and oligospheres (spheres enriched with oligodendrocyte-lineage cells) derived from the iPSCs by liquid chromatography-mass spectrometry showed accumulation of ether phospholipids in the Sjögren-Larsson patient-derived neurospheres and oligospheres. The results are consistent with the previously reported accumulation of ether lipids in the postmortem brain tissue of an SLS patient. Therefore, iPSCs and iPSC-derived neurospheres and oligospheres established from SLS patients can be useful tools for future pathological analysis of the central nervous system pathophysiology in SLS.
斯-约二氏综合征（Sjögren-Larsson syndrome，SLS）是一种常染色体隐性脑白质营养不良，其特征为鱼鳞癣、智力障碍和进行性痉挛性瘫痪，病因是编码脂肪酸醛脱氢酶（fatty aldehyde dehydrogenase，FALDH）的 ALDH3A2 基因的双等位致病性变异，FALDH 催化多种参与脂肪酸醛氧化的代谢反应。仅有少数研究对 SLS 患者的脂质谱进行了测定。在先前对一名 65 岁 SLS 患者的大脑进行的尸检研究中，脂质组学分析显示，在白质和灰质中长链不饱和醚脂质种类的积累。在本研究中，我们使用源自 SLS 患者的神经元和少突胶质细胞谱系细胞建立了疾病模型，以分析 SLS 中的脂质代谢和基因表达谱。为此，我们从两位具有已知 ALDH3A2 致病性变异的 SLS 表型患者中生成了诱导多能干细胞（induced pluripotent stem cells，iPSCs）：一位是复合杂合子（c.1339A>G：p.（Lys447Glu）和 c.57_132dup：p.（Ile45Serfs*34）），另一位是纯合子（c.1339A>G：p.（Lys447Glu））。从两位患者建立的 SLS-iPSC 系中，FALDH 活性几乎为零。通过液相色谱-质谱法对源自 iPSCs 的神经球和少突胶质细胞球（富含少突胶质细胞谱系细胞的球体）进行磷脂分析显示，在 Sjögren-Larsson 患者来源的神经球和少突胶质细胞球中醚磷脂的积累。结果与先前报道的 SLS 患者脑组织中醚脂质的积累一致。因此，源自 SLS 患者的 iPSCs 及其衍生的神经球和少突胶质细胞球可以成为 SLS 中枢神经系统病理生理学未来病理分析的有用工具。
