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

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.

Primary adrenal insufficiency: New genetic causes and their long‐term consequences

“…Disruption of this enzyme can lead to an accumulation of sphingolipids and ceramide and represents a novel sphingolipidosis (similar to Fabry disease, Gaucher disease and Niemann‐Pick disease; Figure A). Other clinical features reported in these patients include ichthyosis, neurological dysfunction, dyslipidaemia, lymphopaenia and other endocrine features such as primary hypothyroidism and cryptorchidism . The adrenal features are not invariable at presentation and may be masked by steroid treatment for nephrotic syndrome or precipitated by steroid withdrawal.…”

“…Another recent discovery is the association of PAI with steroid‐resistant nephrotic syndrome, due to homozygous or compound heterozygous variants in sphingosine‐1‐phosphate lyase‐1 (SGPL1) …”

“…Another recent discovery is the association of PAI with steroid-resistant nephrotic syndrome, due to homozygous or compound heterozygous variants in sphingosine-1-phosphate lyase-1 (SGPL1). [67][68][69] SGPL1 is an enzyme that catalyses the breakdown of sphingolipids by cleaving sphingosine-1-phosphate. 67 Figure 4B).…”

“…[67][68][69] SGPL1 is an enzyme that catalyses the breakdown of sphingolipids by cleaving sphingosine-1-phosphate. 67 Figure 4B). In patients, adrenal calcifications can sometimes be seen on imaging.…”

Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans

“…Mutations in the GM3 synthase gene ST3GAL5 were associated with refractory epilepsy, myoclonus, generalized tonic-clonic seizures, psychomotor delay, developmental stagnation, blindness, and deafness due to an increase in LacCer and other gangliosides (OMIM #609056) 13,14 , whereas defects in the GM2/GD2 synthase (B4GALNT1) lead to GM3 accumulation and a complex form of hereditary spastic paraplegia with cognitive impairment and seizures (OMIM #609195) 15 . Recently, mutations in SGPL1 were associated with a spectrum of disease phenotypes 16,17,18 including recessive steroid-resistant nephrotic syndrome (SRNS), ichthyosis, adrenal insufficiency, immunodeficiency and brain defects (OMIM #617575). In addition, SGPL1 mutations were found in a family with Charcot-Marie-Tooth neuropathy (CMT).…”