Miniatura

Fitxers

LovricS.pdf (6.26 MB)

Tipus de document

Article

Versió

Versió publicada

Data de publicació

2017-03-01

Tots els drets reservats

Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/124482

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

Títol de la revista

Autors

Director/Tutor

ISSN de la revista

Títol del volum

Recurs relacionat

https://doi.org/10.1172/JCI89626

Resum

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1. yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

Matèries

Síndrome nefròtica, Insuficiència renal crònica

Matèries (anglès)

Nephrotic syndrome, Chronic renal failure

Citació

Col·leccions

Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
<b>Publicacions de projectes de recerca finançats per la UE</b>

Citació

LOVRIC, Svjetlana, GONCALVES, Sara, GEE, Heon yungy, OSKOUIAN, Babak, SRINIVAS, Honnappa, CHOI, Won-il, SHRIL, Shirlee, ASHRAF, Shazia, TAN, Weizhen, RAO, Jia, AIRIK, Merlin, SCHAPIRO, David, BRAUN, Daniela a., SADOWSKI, Carolin e., WIDMEIER, Eugen, JOBST-SCHWAN, Tilman, SCHMIDT, Johanna magdalena, GIRIK, Vladimir, CAPITANI, Guido, SUH, Jung h., LACHAUSSÉE, Noëlle, ARRONDEL, Christelle, PATAT, Julie, GRIBOUVAL, Olivier, FURLANO, Monica, BOYER, Olivia, SCHMITT, Alain, VUIBLET, Vincent, HASHMI, Seema, WILCKEN, Rainer, BERNIER, Francois p., INNES, A. micheil, PARBOOSINGH, Jillian s., LAMONT, Ryan e., MIDGLEY, Julian p., WRIGHT, Nicola, MAJEWSKI, Jacek, ZENKER, Martin, SCHAEFER, Franz, KUSS, Navina, GREIL, Johann, GIESE, Thomas, SCHWARZ, Klaus, CATHELINE, Vilain, SCHANZE, Denny, FRANKE, Ingolf, SZNAJER, Yves, TRUANT, Anne s., ADAMS, Brigitte, DESIR, Julie, BIEMANN, Ronald, PEI, York, ARS, Elisabet, LLOBERAS BLANCH, Núria, MADRID, Alvaro, DHARNIDHARKA, Vikas r., CONNOLLY, Anne m., WILLING, Marcia c., COOPER, Megan a., LIFTON, Richard p, SIMONS, Matias, RIEZMAN, Howard, ANTIGNAC, Corinne, SABA, Julie d., HILDEBRANDT, Friedhelm. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. _Journal of Clinical Investigation_. 2017. Vol. 127, núm. 3, pàgs. 912-928. [consulta: 23 de gener de 2026]. [Disponible a: https://hdl.handle.net/2445/124482]

Exportar metadades

JSON - METS

Compartir registre