吡哆醇补充改善小鼠 SGPL1 R222Q 变异型鞘氨醇磷酸裂解酶缺乏综合征
Pyridoxine supplementation amelioratesSGPL1 R222Q variant sphingosine phosphate lyase insufficiency syndrome in mice
鞘氨醇磷酸裂解酶缺乏综合征（SPLIS）是一种罕见遗传病，可导致肾病综合征和神经病变，由 SGPL1 基因突变引起，该基因编码的酶需要维生素 B6 活性形式作为辅因子。研究者先在一名 R222Q 变异患者中观察到补充吡哆醇（维生素 B6 前体）后神经症状改善、血浆鞘氨醇-1-磷酸恢复正常。随后用基因编辑构建了对应小鼠模型：喂含吡哆醇饲料的小鼠无明显异常，而喂低吡哆醇饲料的小鼠出现蛋白尿和肾小球硬化，并发现足细胞丢失。阻断鞘氨醇-1-磷酸生成或相关信号通路可防止肾损伤。该研究建立了疾病模型并提示辅因子补充的治疗潜力，但仍属动物实验阶段。
为什么推荐给您：首次建立该变异型动物模型并证明维生素 B6 补充有效，属有转化前景的新机制证据。
不需要生物学背景，多打比方
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摘要Abstract
Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare condition causing nephrotic syndrome, neuropathy, and other manifestations. SPLIS is caused by mutations in SGPL1, which encodes sphingosine-1-phosphate lyase (SPL), a pyridoxal 5'-phosphate (PLP)-dependent enzyme needed to degrade the bioactive sphingolipid sphingosine-1-phosphate (S1P). Supplementation with the PLP precursor pyridoxine benefits some individuals with PLP-dependent enzymopathies. We investigated whether pyridoxine has therapeutic activity in SPLIS. Neurological improvement, plasma S1P normalization, and increased SPL activity in patient-derived fibroblasts were observed after pyridoxine supplementation in a patient with R222Q-variant SPLIS. Additionally, PLP dose-dependently augmented recombinant R222Q-variant SPL activity. To further explore pyridoxine's effects, gene editing was employed to create an R222Q-variant SPLIS mouse model. SPLR222Q mice fed pyridoxine-enriched chow lacked obvious phenotypes. However, SPL inactivation, S1P accumulation, proteinuria, and glomerulosclerosis developed in SPLR222Q but not WT mice fed chow with reduced pyridoxine. Ultrastructural analysis and super-resolution microscopy showed podocyte loss and foot process effacement. Transcriptional profiling revealed patterns of cytokine upregulation and extracellular matrix remodeling. Inhibiting S1P production or RhoA/ROCK signaling prevented nephrosis in SPLR222Q mice fed chow lacking pyridoxine. Our findings establish a SPLIS mouse model that recapitulates R222Q-variant SPLIS, demonstrates its responsiveness to pyridoxine, and implicates a S1P/RhoA/ROCK pathway in its pathophysiology. Running Title: Cofactor supplementation in R222Q-variant SPLIS.