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Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2017 Mar 01; Vol. 127 (3), pp. 942-953. Date of Electronic Publication: 2017 Feb 06. - Publication Year :
- 2017
-
Abstract
- 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.
- Subjects :
- Adrenal Glands enzymology
Adrenal Glands pathology
Adrenal Insufficiency enzymology
Adrenal Insufficiency genetics
Adrenal Insufficiency pathology
Aldehyde-Lyases metabolism
Animals
HEK293 Cells
Humans
Kidney enzymology
Kidney pathology
Mice
Mice, Knockout
Nephrotic Syndrome enzymology
Nephrotic Syndrome pathology
Adrenal Insufficiency congenital
Aldehyde-Lyases genetics
Homozygote
INDEL Mutation
Mutation, Missense
Nephrotic Syndrome genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 127
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 28165343
- Full Text :
- https://doi.org/10.1172/JCI90171