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

PRASAD, RATHI; HADJIDEMETRIOU, IRENE; MAHARAJ, AVINAASH; MEIMARIDOU, EIRINI; BUONOCORE, FEDERICA; SALEEM, MOIN; HURCOMBE, JENNY; BIERZYNSKA, AGNIESZKA; BARBAGELATA, ELIANA; BERGADÁ, IGNACIO; CASSINELLI, HAMILTON; DAS, URMI; KRONE, RUTH; HACIHAMDIOGLU, BULENT; SARI, ERKAN; YESILKAYA, EDIZ; STORR, HELEN L.; CLEMENTE, MARIA; FERNANDEZ-CANCIO, MONICA; CAMATS, NURIA; RAM, NANIK; ACHERMANN, JOHN C.; VAN VELDHOVEN, PAUL P.; GUASTI, LEONARDO; BRASLAVSKY, DEBORA; GURAN, TULAY; METHERELL, LOUISE A.

JOURNAL OF CLINICAL INVESTIGATION

AMER SOC CLINICAL INVESTIGATION INC

Año: 2017 vol. 127 p. 942 - 953

0021-9738

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-offunctionmutations in sphingosine-1-phosphate lyase (SGPL1). SGPL1 executes the final decisive step of the sphingolipidbreakdown 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 differenthomozygous 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 manifestedother features, including ichthyosis, primary hypothyroidism, neurological symptoms, and cryptorchidism. Sgpl1?/? micerecapitulated the main characteristics of the human disease with abnormal adrenal and renal morphology. Sgpl1?/? micedisplayed disrupted adrenocortical zonation and defective expression of steroidogenic enzymes as well as renal histology inkeeping with a glomerular phenotype. In summary, we have identified SGPL1 mutations in humans that perhaps represent adistinct multisystemic disorder of sphingolipid metabolism.