Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.
Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.
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DOI：
10.1172/jci90171
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Metherell LA
中科院分区：
文献类型：
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作者：
Prasad R;Hadjidemetriou I;Maharaj A;Meimaridou E;Buonocore F;Saleem M;Hurcombe J;Bierzynska A;Barbagelata E;Bergadá I;Cassinelli H;Das U;Krone R;Hacihamdioglu B;Sari E;Yesilkaya E;Storr HL;Clemente M;Fernandez-Cancio M;Camats N;Ram N;Achermann JC;Van Veldhoven PP;Guasti L;Braslavsky D;Guran T;Metherell LA
原发性肾上腺功能不全可危及生命，可单独或与其他合并症合并出现。在这里，我们描述了一个原发性肾上腺皮质功能不全综合征和类固醇耐药肾病综合征引起的功能丧失突变鞘氨醇-1-磷酸裂解酶（SGPL 1）。SGPL 1执行鞘脂分解途径的最后决定性步骤，介导脂质信号分子鞘氨醇-1-磷酸（S1 P）的不可逆裂解。该途径的其他上游组分的突变导致溶酶体鞘脂物质的有害积累，这与一系列称为鞘脂病的病症相关。在这项工作中，我们已经确定了4个不同的纯合突变，c.665G>A（p.R222Q），c.1633_1635delTTC（p.F545del），c.261+1G>A（p.S65Rfs*6）和c.7dupA（p.S3Kfs*11），在5个家庭的条件。总共有8名患者接受了调查，其中一些人还表现出其他特征，包括鱼鳞病，原发性甲状腺功能减退症，神经系统症状和隐睾症。sgpl 1-/-小鼠概括了人类疾病的主要特征，肾上腺和肾脏形态异常。sgpl 1-/-小鼠显示肾上腺皮质分区破坏和类固醇生成酶的表达缺陷，以及肾组织学与肾小球表型一致。总之，我们已经确定了SGPL 1突变在人类中，可能代表一个独特的多系统性疾病的鞘脂代谢。
Primary adrenal insufficiency is life threatening and can present alone or in combination with other comorbidities. Here, we have described a primary adrenal insufficiency syndrome and steroid-resistant nephrotic syndrome caused by loss-of-function mutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipid breakdown pathway, mediating the irreversible cleavage of the lipid-signaling molecule sphingosine-1-phosphate (S1P). Mutations in other upstream components of the pathway lead to harmful accumulation of lysosomal sphingolipid species, which are associated with a series of conditions known as the sphingolipidoses. In this work, we have identified 4 different homozygous mutations, c.665G>A (p.R222Q), c.1633_1635delTTC (p.F545del), c.261+1G>A (p.S65Rfs*6), and c.7dupA (p.S3Kfs*11), in 5 families with the condition. In total, 8 patients were investigated, some of whom also manifested other features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1–/– mice recapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1–/– mice displayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology in keeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent a distinct multisystemic disorder of sphingolipid metabolism.
影响因子：
2.7
作者：
Ram N;Asghar A;Islam N
通讯作者：
Islam N