期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 3, 页码 942-953出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI90171
关键词
-
资金
- Medical Research Council UK [MR/K020455/1]
- Wellcome Trust [WT095984AIA, 098513/Z/12/Z]
- Biotechnology and Biological Sciences Research Council [BB/L002671/1]
- Rosetrees Trust
- Joint MRC/Wellcome Trust [099175/Z/12/Z]
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children (GOSH) NHS Foundation Trust and University College London
- National Institute for Health Research Biomedical Research Centre (NIHR BRC) at the GOSH NHS Foundation Trust
- UCL Great Ormond Street Institute of Child Health
- Wellcome Trust [099175/Z/12/Z] Funding Source: Wellcome Trust
- BBSRC [BB/L002671/1] Funding Source: UKRI
- MRC [MC_PC_15004, G0700089, G0801265, MR/K020455/1] Funding Source: UKRI
- Barts Charity [MGU0361] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/L002671/1] Funding Source: researchfish
- Medical Research Council [MC_PC_15004, MR/K020455/1, G0700089, G0801265] Funding Source: researchfish
- Rosetrees Trust [M355] Funding Source: researchfish
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-offunction 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据