CEDIE   05498
CENTRO DE INVESTIGACIONES ENDOCRINOLOGICAS "DR. CESAR BERGADA"
Unidad Ejecutora - UE
artículos
Título:
Sphingosine-1-phosphate lyase mutations cause primary adrenal insufficiency and steroid-resistant nephrotic syndrome
Autor/es:
METHERELL, LOUISE A.; GUASTI, LEONARDO; RAM, NANIK; CLEMENTE, MARIA; SARI, ERKAN; DAS, URMI; BARBAGELATA, ELIANA; SALEEM, MOIN; MAHARAJ, AVINAASH; BRASLAVSKY, DEBORA; ACHERMANN, JOHN C.; FERNANDEZ-CANCIO, MONICA; GURAN, TULAY; YESILKAYA, EDIZ; VAN VELDHOVEN, PAUL P.; KRONE, RUTH; CAMATS, NURIA; BERGADÁ, IGNACIO; STORR, HELEN L.; HURCOMBE, JENNY; MEIMARIDOU, EIRINI; HACIHAMDIOGLU, BULENT; PRASAD, RATHI; CASSINELLI, HAMILTON; BIERZYNSKA, AGNIESZKA; BUONOCORE, FEDERICA; HADJIDEMETRIOU, IRENE
Revista:
JOURNAL OF CLINICAL INVESTIGATION
Editorial:
AMER SOC CLINICAL INVESTIGATION INC
Referencias:
Año: 2017 vol. 127 p. 942 - 953
ISSN:
0021-9738
Resumen:
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.