title: Positional cloning uncovers mutations in PLCE1 responsible for a nephrotic syndrome variant that may be reversible.
abstract: 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.
authors.affiliation: Department of Pediatrics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Bernward
authors.initials: B
authors.lastname: Hinkes
authors.forename: Roger C
authors.initials: RC
authors.lastname: Wiggins
authors.forename: Rasheed
authors.initials: R
authors.lastname: Gbadegesin
authors.forename: Christopher N
authors.initials: CN
authors.lastname: Vlangos
authors.forename: Dominik
authors.initials: D
authors.lastname: Seelow
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Puneet
authors.initials: P
authors.lastname: Garg
authors.forename: Rakesh
authors.initials: R
authors.lastname: Verma
authors.forename: Hassan
authors.initials: H
authors.lastname: Chaib
authors.forename: Bethan E
authors.initials: BE
authors.lastname: Hoskins
authors.forename: Shazia
authors.initials: S
authors.lastname: Ashraf
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.forename: Meera
authors.initials: M
authors.lastname: Goyal
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Wharram
authors.forename: Asher D
authors.initials: AD
authors.lastname: Schachter
authors.forename: Sudha
authors.initials: S
authors.lastname: Mudumana
authors.forename: Iain
authors.initials: I
authors.lastname: Drummond
authors.forename: Dontscho
authors.initials: D
authors.lastname: Kerjaschki
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Waldherr
authors.forename: Alexander
authors.initials: A
authors.lastname: Dietrich
authors.forename: Fatih
authors.initials: F
authors.lastname: Ozaltin
authors.forename: Aysin
authors.initials: A
authors.lastname: Bakkaloglu
authors.forename: Roxana
authors.initials: R
authors.lastname: Cleper
authors.forename: Lina
authors.initials: L
authors.lastname: Basel-Vanagaite
authors.forename: Martin
authors.initials: M
authors.lastname: Pohl
authors.forename: Martin
authors.initials: M
authors.lastname: Griebel
authors.forename: Alexey N
authors.initials: AN
authors.lastname: Tsygin
authors.forename: Alper
authors.initials: A
authors.lastname: Soylu
authors.forename: Dominik
authors.initials: D
authors.lastname: Müller
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Sorli
authors.forename: Tom D
authors.initials: TD
authors.lastname: Bunney
authors.forename: Matilda
authors.initials: M
authors.lastname: Katan
authors.forename: Jinhong
authors.initials: J
authors.lastname: Liu
authors.forename: Massimo
authors.initials: M
authors.lastname: Attanasio
authors.forename: John F
authors.initials: JF
authors.lastname: O'toole
authors.forename: Katrin
authors.initials: K
authors.lastname: Hasselbacher
authors.forename: Bettina
authors.initials: B
authors.lastname: Mucha
authors.forename: Edgar A
authors.initials: EA
authors.lastname: Otto
authors.forename: Rannar
authors.initials: R
authors.lastname: Airik
authors.forename: Andreas
authors.initials: A
authors.lastname: Kispert
authors.forename: Grant G
authors.initials: GG
authors.lastname: Kelley
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.forename: Thomas
authors.initials: T
authors.lastname: Gudermann
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Holzman
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Friedhelm
authors.initials: F
authors.lastname: Hildebrandt
mesh_terms: 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
chemical_list: D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon