Mutations in PLCE1 are a major cause of isolated diffuse mesangial sclerosis (IDMS).
OBJECTIVE
Diffuse mesangial sclerosis (DMS) is a histologically distinct variant of nephrotic syndrome (NS) that is characterized by early onset and by progression to end-stage kidney disease (ESKD). Besides syndromic DMS, isolated (non-syndromic) DMS (IDMS) has been described. The etiology and pathogenesis of DMS is not understood. We recently identified by positional cloning recessive mutations in the gene PLCE1/NPHS3 as a novel cause of IDMS. We demonstrated a role of PLCE1 in glomerulogenesis. Mutations in two other genes WT1 and LAMB2 may also cause IDMS. We therefore determine in this study the relative frequency of mutations in PLCE1, WT1 or LAMB2 as the cause of IDMS in a worldwide cohort.


METHODS
We identified 40 children from 35 families with IDMS from a worldwide cohort of 1368 children with NS. All the subjects were analyzed for mutations in all exons of PLCE1 by multiplex capillary heteroduplex analysis and direct sequencing, by direct sequencing of exons 8 and 9 of WT1, and all the exons of LAMB2.


RESULTS
The median (range) age at onset of NS was 11 (1-72) months. We detected truncating mutations in PLCE1 in 10/35 (28.6%) families and WT1 mutations in 3/35 (8.5%) families. We found no mutations in LAMB2.


CONCLUSIONS
PLCE1 mutation is the most common cause of IDMS in this cohort. We previously reported that one child with truncating mutation in PLCE1 responded to cyclosporine therapy. If this observation is confirmed in a larger study, mutations in PLCE1 may serve as a biomarker for selecting patients with IDMS who may benefit from treatment.
Departments of Pediatrics and of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
Rasheed
R
Gbadegesin
Bernward G
BG
Hinkes
Bethan E
BE
Hoskins
Christopher N
CN
Vlangos
Saskia F
SF
Heeringa
Jinhong
J
Liu
Chantal
C
Loirat
Fatih
F
Ozaltin
Seema
S
Hashmi
Francis
F
Ulmer
Roxanna
R
Cleper
Robert
R
Ettenger
Corinne
C
Antignac
Roger C
RC
Wiggins
Martin
M
Zenker
Friedhelm
F
Hildebrandt
D001706:Biopsy; D002675:Child, Preschool; D004247:DNA; D004252:DNA Mutational Analysis; D005091:Exons; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005920:Glomerular Mesangium / Q000473:pathology*; D006801:Humans; D007223:Infant; D007797:Laminin / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation; D009400:Nephrosclerosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D054801:Phosphoinositide Phospholipase C / Q000235:genetics* / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011379:Prognosis; D012720:Severity of Illness Index; D025721:WT1 Proteins / Q000235:genetics / Q000378:metabolism
D007797:Laminin; D025721:WT1 Proteins; C058783:laminin beta2; D004247:DNA; D054801:Phosphoinositide Phospholipase C; C423320:phospholipase C epsilon