Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.
Nephrotic syndrome, a malfunction of the kidney glomerular filter, leads to proteinuria, edema and, in steroid-resistant nephrotic syndrome, end-stage kidney disease. Using positional cloning, we identified mutations in the phospholipase C epsilon gene (PLCE1) as causing early-onset nephrotic syndrome with end-stage kidney disease. Kidney histology of affected individuals showed diffuse mesangial sclerosis (DMS). Using immunofluorescence, we found PLCepsilon1 expression in developing and mature glomerular podocytes and showed that DMS represents an arrest of normal glomerular development. We identified IQ motif-containing GTPase-activating protein 1 as a new interaction partner of PLCepsilon1. Two siblings with a missense mutation in an exon encoding the PLCepsilon1 catalytic domain showed histology characteristic of focal segmental glomerulosclerosis. Notably, two other affected individuals responded to therapy, making this the first report of a molecular cause of nephrotic syndrome that may resolve after therapy. These findings, together with the zebrafish model of human nephrotic syndrome generated by plce1 knockdown, open new inroads into pathophysiology and treatment mechanisms of nephrotic syndrome.
Hinkes
Bernward
B
Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
Wiggins
Roger C
RC
Gbadegesin
Rasheed
R
Vlangos
Christopher N
CN
Seelow
Dominik
D
Nürnberg
Gudrun
G
Garg
Puneet
P
Verma
Rakesh
R
Chaib
Hassan
H
Hoskins
Bethan E
BE
Ashraf
Shazia
S
Becker
Christian
C
Hennies
Hans Christian
HC
Goyal
Meera
M
Wharram
Bryan L
BL
Schachter
Asher D
AD
Mudumana
Sudha
S
Drummond
Iain
I
Kerjaschki
Dontscho
D
Waldherr
Rüdiger
R
Dietrich
Alexander
A
Ozaltin
Fatih
F
Bakkaloglu
Aysin
A
Cleper
Roxana
R
Basel-Vanagaite
Lina
L
Pohl
Martin
M
Griebel
Martin
M
Tsygin
Alexey N
AN
Soylu
Alper
A
Müller
Dominik
D
Sorli
Caroline S
CS
Bunney
Tom D
TD
Katan
Matilda
M
Liu
Jinhong
J
Attanasio
Massimo
M
O'toole
John F
JF
Hasselbacher
Katrin
K
Mucha
Bettina
B
Otto
Edgar A
EA
Airik
Rannar
R
Kispert
Andreas
A
Kelley
Grant G
GG
Smrcka
Alan V
AV
Gudermann
Thomas
T
Holzman
Lawrence B
LB
Nürnberg
Peter
P
Hildebrandt
Friedhelm
F
D000818:Animals; D002648:Child; D002675:Child, Preschool; D003001:Cloning, Molecular; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D007668:Kidney / Q000201:enzymology / Q000473:pathology; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020125:Mutation, Missense; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D054801:Phosphoinositide Phospholipase C; D051381:Rats; D017384:Sequence Deletion; D010738:Type C Phospholipases / Q000235:genetics*; D015027:Zebrafish / Q000235:genetics
D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon