Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Commun Biol. 2023 Dec 21;6(1):1298. doi: 10.1038/s42003-023-05665-6.
Biallelic mutations of the chromatin regulator SMARCAL1 cause Schimke Immunoosseous Dysplasia (SIOD), characterized by severe growth defects and premature mortality. Atherosclerosis and hyperlipidemia are common among SIOD patients, yet their onset and progression are poorly understood. Using an integrative approach involving proteomics, mouse models, and population genetics, we investigated SMARCAL1's role. We found that SmarcAL1 interacts with angiopoietin-like 3 (Angptl3), a key regulator of lipoprotein metabolism. In vitro and in vivo analyses demonstrate SmarcAL1's vital role in maintaining cellular lipid homeostasis. The observed translocation of SmarcAL1 to cytoplasmic peroxisomes suggests a potential regulatory role in lipid metabolism through gene expression. SmarcAL1 gene inactivation reduces the expression of key genes in cellular lipid catabolism. Population genetics investigations highlight significant associations between SMARCAL1 genetic variations and body mass index, along with lipid-related traits. This study underscores SMARCAL1's pivotal role in cellular lipid metabolism, likely contributing to the observed lipid phenotypes in SIOD patients.
双等位基因突变导致染色质调控因子 SMARCAL1 引起 Schimke 免疫骨发育不良（SIOD），其特征是严重的生长缺陷和过早死亡。动脉粥样硬化和高脂血症在 SIOD 患者中很常见，但它们的发病和进展尚不清楚。我们使用涉及蛋白质组学、小鼠模型和群体遗传学的综合方法研究了 SMARCAL1 的作用。我们发现 SmarcAL1 与血管生成素样 3（Angptl3）相互作用，Angptl3 是脂蛋白代谢的关键调节剂。体外和体内分析表明 SmarcAL1 在维持细胞脂质稳态中起着至关重要的作用。观察到 SmarcAL1 易位到细胞质过氧化物酶体表明它可能通过基因表达在脂质代谢中发挥调节作用。SmarcAL1 基因失活会降低细胞脂质分解代谢的关键基因的表达。群体遗传学研究强调了 SMARCAL1 遗传变异与体重指数以及与脂质相关特征之间的显著关联。这项研究强调了 SMARCAL1 在细胞脂质代谢中的关键作用，可能导致 SIOD 患者中观察到的脂质表型。
