Mutations in podocyte genes are a rare cause of primary FSGS associated with ESRD in adult patients.
OBJECTIVE
Several genes have been identified to be causative for the disease in a subset of patients with focal segmental glomerulosclerosis (FSGS) and nephrotic syndrome (NS). Mutations in genes with autosomal dominant inheritance mostly affect adolescent or adult patients. In rare cases recessive mutations in NPHS2 are associated with late-onset FSGS. Hereditary FSGS is associated with poor renal survival and low rates of disease recurrence after renal transplantation. Aim of the study was to evaluate the incidence of gene mutations within a cohort of adult patients with primary FSGS and/or NS and progression to end-stage renal disease (ESRD).


METHODS
Genotyping for TRPC6, ACTN4, CD2AP, WT1, INF2, NPHS2 and NPHS1 was performed in all patients with primary FSGS and ESRD registered on the waiting list for kidney transplantation of a large German transplant center (n = 26 out of 478 registered patients). Mean age at onset was 31.7 years; a positive family history for renal disease was documented in 11 (42%) patients, of these one with familiar history of FSGS.


RESULTS
A missense mutation (p.R360H) was identified in TRPC6, 2 missense mutations in compound heterozygous state in NPHS1 (p.P368L; p.G412C), a sequence variation of unknown significance (p.R310Q) in ACTN4 and the non-neutral NPHS2 polymorphism p.R229Q in two additional patients. No mutations were detected in INF2, CD2AP and WT1.


CONCLUSIONS
The observed mutation rate was 8% in this single-center cohort of adult patients with primary FSGS. Mutations in podocyte genes seem to be a rare cause of FSGS and renal failure in adult patients. However, they should be considered as the underlying cause in a subset of patient as the impact on family counseling and patients' life perspectives are significant.
Pediatric Nephrology, Pediatrics II, University-Children's Hospital Essen, Germany. anja.buescher@uk-essen.de
Anja K
AK
Büscher
Martin
M
Konrad
Mato
M
Nagel
Oliver
O
Witzke
Andreas
A
Kribben
Peter F
PF
Hoyer
Stefanie
S
Weber
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005858:Germany; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D050199:Podocytes / Q000737:chemistry* / Q000473:pathology; D011110:Polymorphism, Genetic; D012042:Registries; D014850:Waiting Lists; D055815:Young Adult