Sphingosine‐1‐phosphate (S1P) lyase is a vitamin B6‐dependent enzyme that degrades sphingosine‐1‐phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14). Patients with SPLIS exhibit lymphopenia, nephrosis, adrenal insufficiency, and/or neurological defects. No targeted therapy for SPLIS has been reported. Vitamin B6 supplementation has therapeutic activity in some genetic diseases involving B6‐dependent enzymes, a finding ascribed largely to the vitamin's chaperone function. We investigated whether B6 supplementation might have activity in SPLIS patients. We retrospectively monitored responses of disease biomarkers in patients supplemented with B6 and measured SPL activity and sphingolipids in B6‐treated patient‐derived fibroblasts. In two patients, disease biomarkers responded to B6 supplementation. S1P abundance and activity levels increased and sphingolipids decreased in response to B6. One responsive patient is homozygous for an SPL R222Q variant present in almost 30% of SPLIS patients. Molecular modeling suggests the variant distorts the dimer interface which could be overcome by cofactor supplementation. We demonstrate the first potential targeted therapy for SPLIS and suggest that 30% of SPLIS patients might respond to cofactor supplementation.

中文翻译：

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磷酸鞘氨醇裂解酶不足综合征对补充维生素 B6 辅因子的反应。


1-磷酸鞘氨醇 (S1P) 裂解酶是一种维生素 B6 依赖性酶，可在鞘脂代谢的最后一步降解 1-磷酸鞘氨醇。 2017 年，一种新的遗传性疾病被描述为由SGPL1突变引起，SGPL1 编码磷酸鞘氨醇裂解酶 (SPL)。这种情况称为 SPL 不足综合征 (SPLIS) 或 14 型肾病综合征 (NPHS14)。 SPLIS 患者表现出淋巴细胞减少、肾病、肾上腺功能不全和/或神经系统缺陷。目前尚无 SPLIS 靶向治疗的报道。维生素 B6 补充剂对某些涉及 B6 依赖性酶的遗传性疾病具有治疗活性，这一发现很大程度上归因于维生素的伴侣功能。我们研究了维生素 B6 补充剂是否对 SPLIS 患者有效。我们回顾性监测补充 B6 的患者疾病生物标志物的反应，并测量 B6 治疗的患者来源的成纤维细胞中的 SPL 活性和鞘脂。在两名患者中，疾病生物标志物对维生素 B6 补充剂有反应。 B6 导致 S1P 丰度和活性水平增加，鞘脂减少。一名有反应的患者是 SPL R222Q 变异纯合子，该变异存在于近 30% 的 SPLIS 患者中。分子模型表明该变体扭曲了二聚体界面，这可以通过补充辅因子来克服。我们展示了第一个潜在的 SPLIS 靶向治疗，并表明 30% 的 SPLIS 患者可能对辅因子补充有反应。