Journal Article

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

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

2017

Overview

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.

• Publisher: American Society for Clinical Investigation
• Subject: Adrenal Glands - enzymology / Adrenal Glands - pathology / Adrenal Insufficiency - congenital / Adrenal Insufficiency - enzymology / Adrenal Insufficiency - genetics / Adrenal Insufficiency - pathology / Age / Aldehyde-Lyases - genetics / Aldehyde-Lyases - metabolism / Animals / Biomedical research / Defects / Ethics / Gene expression / Gene mutation / Genetic aspects / HEK293 Cells / Homozygote / Hospitals / Humans / INDEL Mutation / Kidney - enzymology / Kidney - pathology / Laboratories / Medical research / Mice / Mice, Knockout / Mutation / Mutation, Missense / Nephrotic syndrome / Nephrotic Syndrome - enzymology / Nephrotic Syndrome - genetics / Nephrotic Syndrome - pathology / Patients / Physiological aspects / Risk factors / Rodents / Siblings / Sphingosine / Studies