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Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome
Rathi Prasad, … , Tulay Guran, Louise A. Metherell
Rathi Prasad, … , Tulay Guran, Louise A. Metherell
Published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):942-953. https://doi.org/10.1172/JCI90171.
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Research Article Endocrinology Genetics

Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome

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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.

Authors

Rathi Prasad, Irene Hadjidemetriou, Avinaash Maharaj, Eirini Meimaridou, Federica Buonocore, Moin Saleem, Jenny Hurcombe, Agnieszka Bierzynska, Eliana Barbagelata, Ignacio Bergadá, Hamilton Cassinelli, Urmi Das, GOSgene, Ruth Krone, Bulent Hacihamdioglu, Erkan Sari, Ediz Yesilkaya, Helen L. Storr, Maria Clemente, Monica Fernandez-Cancio, Nuria Camats, Nanik Ram, John C. Achermann, Paul P. Van Veldhoven, Leonardo Guasti, Debora Braslavsky, Tulay Guran, Louise A. Metherell

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Figure 1

Pedigrees of kindreds 1 to 5 where all affected individuals manifested PAI, with or without SRNS, and were positive for mutations in SGPL1.

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Pedigrees of kindreds 1 to 5 where all affected individuals manifested P...
Black symbols indicate individuals with PAI alone, half-filled in green indicate those who additionally had steroid-resistant nephrotic syndrome, and green indicate those with SRNS alone. All affected individuals were homozygous for the indicated mutations (patients sequenced have been numbered from 1 to 8), and parents were heterozygous (those sequenced denoted by gray symbols). Mutations for patients 2, 3, and 5 were identified by WES and the remainder by Sanger sequencing of SGPL1.
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