Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism.
Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism.
复制标题
DOI：
10.1016/j.jbior.2018.09.004
复制
发表时间：
2019-01
影响因子：
--
通讯作者：
Saba JD
中科院分区：
文献类型：
--
作者：
Choi YJ;Saba JD
鞘氨醇-1-磷酸裂解酶（SPL）是一种细胞内酶，控制鞘脂降解途径中的最后一步，是除去鞘脂的唯一生化途径。具体而言，SPL催化1-磷酸鞘氨醇（S1 P）在C2-3碳键处的裂解，导致其不可逆降解为磷酸乙醇胺（PE）和十六烯醛。反应的底物S1 P是一种生物活性鞘脂代谢物，通过一个由五种G蛋白偶联的S1 P受体（S1 PR）组成的家族发出信号，介导生物活性，包括细胞迁移、细胞存活/死亡/增殖和细胞挤出，从而促进发育、生理功能和疾病的病理生理学（当调节不当时）。2017年，包括我们在内的几个研究小组报告了一种新型儿童综合征，其表现广泛，包括胎儿水肿、类固醇耐药肾病综合征（SRNS）、原发性肾上腺皮质功能不全（派）、快速或隐匿性神经功能恶化、免疫缺陷、棘皮症和内分泌异常。在所有病例中，该疾病均归因于人SGPL 1基因的隐性突变。我们现在把这种情况称为SPL不足综合征，或SPLIS。这种新的鞘脂病的一些特征是通过作为脊椎动物SPLIS疾病模型的Sgpl 1纯合无效小鼠的报告表型预测的。然而，其他SPLIS功能揭示了SPL在人体生理学中以前未被认识到的作用。在这篇综述中，我们简要总结了SPL的生物化学，功能和调节，SPLIS的主要临床和生化特征，以及从小鼠和细胞模型中了解这种情况的病理生理学。最后，我们考虑了治疗SPLIS患者的潜在治疗策略。
Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids. Specifically, SPL catalyzes the cleavage of sphingosine 1-phosphate (S1P) at the C2–3 carbon bond, resulting in its irreversible degradation to phosphoethanolamine (PE) and hexadecenal. The substrate of the reaction, S1P, is a bioactive sphingolipid metabolite that signals through a family of five G protein-coupled S1P receptors (S1PRs) to mediate biological activities including cell migration, cell survival/death/proliferation and cell extrusion, thereby contributing to development, physiological functions and — when improperly regulated — the pathophysiology of disease. In 2017, several groups including ours reported a novel childhood syndrome that featured a wide range of presentations including fetal hydrops, steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency (PAI), rapid or insidious neurological deterioration, immunodeficiency, acanthosis and endocrine abnormalities. In all cases, the disease was attributed to recessive mutations in the human SGPL1 gene. We now refer to this condition as SPL Insufficiency Syndrome, or SPLIS. Some features of this new sphingolipidosis were predicted by the reported phenotypes of Sgpl1 homozygous null mice that serve as vertebrate SPLIS disease models. However, other SPLIS features reveal previously unrecognized roles for SPL in human physiology. In this review, we briefly summarize the biochemistry, functions and regulation of SPL, the main clinical and biochemical features of SPLIS and what is known about the pathophysiology of this condition from murine and cell models. Lastly, we consider potential therapeutic strategies for the treatment of SPLIS patients.
登录
查看更多内容
影响因子：
64.5
作者：
Chipuk JE;McStay GP;Bharti A;Kuwana T;Clarke CJ;Siskind LJ;Obeid LM;Green DR
通讯作者：
Green DR
影响因子：
64.8
作者：
Blaho VA;Galvani S;Engelbrecht E;Liu C;Swendeman SL;Kono M;Proia RL;Steinman L;Han MH;Hla T
通讯作者：
Hla T
影响因子：
9.9
作者：
Atkinson, Derek;Glumac, Jelena Nikodinovic;Jordanova, Albena
通讯作者：
Jordanova, Albena
影响因子：
2.5
作者：
Biswas, S;Biesiada, H;LeVine, SM
通讯作者：
LeVine, SM
影响因子：
--
作者：
Ebenezer DL;Fu P;Suryadevara V;Zhao Y;Natarajan V
通讯作者：
Natarajan V