Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.
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 dpl1Δ 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.
Svjetlana
S
Lovric
Sara
S
Goncalves
Heon Yung
HY
Gee
Babak
B
Oskouian
Honnappa
H
Srinivas
Won-Il
WI
Choi
Shirlee
S
Shril
Shazia
S
Ashraf
Weizhen
W
Tan
Jia
J
Rao
Merlin
M
Airik
David
D
Schapiro
Daniela A
DA
Braun
Carolin E
CE
Sadowski
Eugen
E
Widmeier
Tilman
T
Jobst-Schwan
Johanna Magdalena
JM
Schmidt
Vladimir
V
Girik
Guido
G
Capitani
Jung H
JH
Suh
Noëlle
N
Lachaussée
Christelle
C
Arrondel
Julie
J
Patat
Olivier
O
Gribouval
Monica
M
Furlano
Olivia
O
Boyer
Alain
A
Schmitt
Vincent
V
Vuiblet
Seema
S
Hashmi
Rainer
R
Wilcken
Francois P
FP
Bernier
A Micheil
AM
Innes
Jillian S
JS
Parboosingh
Ryan E
RE
Lamont
Julian P
JP
Midgley
Nicola
N
Wright
Jacek
J
Majewski
Martin
M
Zenker
Franz
F
Schaefer
Navina
N
Kuss
Johann
J
Greil
Thomas
T
Giese
Klaus
K
Schwarz
Vilain
V
Catheline
Denny
D
Schanze
Ingolf
I
Franke
Yves
Y
Sznajer
Anne S
AS
Truant
Brigitte
B
Adams
Julie
J
Désir
Ronald
R
Biemann
York
Y
Pei
Elisabet
E
Ars
Nuria
N
Lloberas
Alvaro
A
Madrid
Vikas R
VR
Dharnidharka
Anne M
AM
Connolly
Marcia C
MC
Willing
Megan A
MA
Cooper
Richard P
RP
Lifton
Matias
M
Simons
Howard
H
Riezman
Corinne
C
Antignac
Julie D
JD
Saba
Friedhelm
F
Hildebrandt
D000446:Aldehyde-Lyases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D002465:Cell Movement / Q000235:genetics*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism; D004331:Drosophila melanogaster; D005260:Female; D006801:Humans; D017490:Ichthyosis, Lamellar / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D050527:Mesangial Cells / Q000201:enzymology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009404:Nephrotic Syndrome / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D021381:Protein Transport / Q000235:genetics; D051381:Rats
D029721:Drosophila Proteins; D000446:Aldehyde-Lyases; C000619494:Sply protein, Drosophila; C022649:sphingosine 1-phosphate lyase (aldolase)