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Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency
- Source :
- Journal of Clinical Investigation, Vol. 127, no.3, p. 912-928 (2017), JOURNAL OF CLINICAL INVESTIGATION, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, Instituto de Salud Carlos III (ISCIII), Dipòsit Digital de la UB, Universidad de Barcelona, Journal of Clinical Investigation, Vol. 127, No 3 (2017) pp. 912-928, Recercat. Dipósit de la Recerca de Catalunya, instname
- Publication Year :
- 2017
- Publisher :
- American Society for Clinical Investigation, 2017.
-
Abstract
- 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.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Nephrotic Syndrome
Nephrosis
030232 urology & nephrology
Síndrome nefròtica
Biology
medicine.disease_cause
Cell Line
03 medical and health sciences
Mice
0302 clinical medicine
Cell Movement
Internal medicine
medicine
Chronic renal failure
Animals
Drosophila Proteins
Humans
Exome sequencing
Immunodeficiency
Aldehyde-Lyases
Mice, Knockout
Mutation
Ichthyosis
General Medicine
medicine.disease
Phenotype
3. Good health
Rats
Protein Transport
030104 developmental biology
Endocrinology
Drosophila melanogaster
ddc:540
Mesangial Cells
Slit diaphragm
Insuficiència renal crònica
Female
Nephrotic syndrome
Ichthyosis, Lamellar
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 00219738
- Database :
- OpenAIRE
- Journal :
- Journal of Clinical Investigation, Vol. 127, no.3, p. 912-928 (2017), JOURNAL OF CLINICAL INVESTIGATION, r-IIB SANT PAU. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica Sant Pau, Instituto de Salud Carlos III (ISCIII), Dipòsit Digital de la UB, Universidad de Barcelona, Journal of Clinical Investigation, Vol. 127, No 3 (2017) pp. 912-928, Recercat. Dipósit de la Recerca de Catalunya, instname
- Accession number :
- edsair.doi.dedup.....49e691abe1f6479437ce05e74e30dfd7