Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications.
We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome (CNS) diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing, two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1-encoding sphingosine-1-phosphate (S1P) lyase 1. SGPL1 catalyzes the irreversible degradation of endogenous and dietary S1P, the final step of sphingolipid catabolism, and of other phosphorylated long-chain bases. S1P is an intracellular and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity. The levels of SGPL1 substrates, S1P, and sphingosine were markedly increased in the patients' blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry. Vascular alterations were present in a patient's renal biopsy, in line with changes seen in Sgpl1 knockout mice that are compatible with a developmental defect in vascular maturation. In conclusion, loss of SGPL1 function is associated with CNS, adrenal calcifications, and hypogonadism.
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.|Division of Human Genetics, Medical University of Innsbruck, Innsbruck, Austria.
Andreas R
AR
Janecke
Department of Medicine, State University of New York (SUNY) at Stony Brook, Stony Brook, New York.|Stony Brook Cancer Center at State University of New York (SUNY) at Stony Brook, Stony Brook, New York.
Ruijuan
R
Xu
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Elisabeth
E
Steichen-Gersdorf
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Siegfried
S
Waldegger
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Andreas
A
Entenmann
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Thomas
T
Giner
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Iris
I
Krainer
Division of Cell Biology, Medical University of Innsbruck, Innsbruck, Austria.
Lukas A
LA
Huber
Division of Histology and Embryology, Medical University of Innsbruck, Innsbruck, Austria.
Michael W
MW
Hess
Division of Pediatric Nephrology, Shaare Zedek Medical Center, Jerusalem, Israel.
Yaacov
Y
Frishberg
Institute of Rare Diseases, Institute of Genetics, Sheba Medical center, Tel Hashomer, Israel.
Hila
H
Barash
Laboratory of Molecular Medicine, Rambam Health Care Campus, Haifa, Israel.|Genomic Research Department, Emedgene Technologies, Tel Aviv, Israel.
Shay
S
Tzur
Genetics Institute, Meir Medical Center, Kfar Saba, Israel.
Nira
N
Schreyer-Shafir
Genetics Institute, Meir Medical Center, Kfar Saba, Israel.|Sackler school of medicine, Tel Aviv University, Ramat Aviv, Israel.
Rivka
R
Sukenik-Halevy
Department of Pathology, Meir Medical center, Kfar Saba, Israel.
Tania
T
Zehavi
Institute of Rare Diseases, Institute of Genetics, Sheba Medical center, Tel Hashomer, Israel.|Sackler school of medicine, Tel Aviv University, Ramat Aviv, Israel.
Annick
A
Raas-Rothschild
Department of Medicine, State University of New York (SUNY) at Stony Brook, Stony Brook, New York.|Stony Brook Cancer Center at State University of New York (SUNY) at Stony Brook, Stony Brook, New York.
Cungui
C
Mao
Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
Thomas
T
Müller
D000307:Adrenal Gland Diseases / Q000151:congenital / Q000201:enzymology / Q000235:genetics*; D000328:Adult; D000446:Aldehyde-Lyases / Q000172:deficiency / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D002114:Calcinosis / Q000201:enzymology / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D006801:Humans; D007223:Infant; D008246:Lysophospholipids / Q000097:blood / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital / Q000201:enzymology / Q000235:genetics*; D010375:Pedigree; D017422:Sequence Analysis, DNA / Q000379:methods; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism
D008246:Lysophospholipids; C060506:sphingosine 1-phosphate; D000446:Aldehyde-Lyases; C022649:sphingosine 1-phosphate lyase (aldolase); D013110:Sphingosine
adrenal calcification; congenital adrenal insufficiency; congenital nephrotic syndrome; developmental; hypergonadotropic hypogonadism; hypogonadism; sphingolipids; sphingosine-1-phosphate; vascular