title: NPHS2 mutation analysis shows genetic heterogeneity of steroid-resistant nephrotic syndrome and low post-transplant recurrence.
abstract: BACKGROUND
  Mutations of NPHS2 are causative in familial autosomal-recessive (AR) and sporadic steroid-resistant nephrotic syndrome (SRNS). This study aimed to determine the spectrum of NPHS2 mutations and to establish genotype-phenotype correlations.
  
  
  METHODS
  NPHS2 mutation analysis was performed in 338 patients from 272 families with SRNS: 81 families with AR SRNS, 172 patients with sporadic SRNS, and 19 patients with diffuse mesangial sclerosis (DMS).
  
  
  RESULTS
  Twenty-six different pathogenic NPHS2 mutations were detected, including 13 novel mutations. The mutation detection rate was 43% for familial AR and 10.5% for sporadic SRNS, confirming genetic heterogeneity. No pathogenic NPHS2 mutations were found in DMS patients. Age at onset in patients with two pathogenic mutations was earlier, especially in cases with frameshift, truncating, and the R138Q missense mutations. Patients with only one NPHS2 mutation or variant had late-onset NS. Triallelic inheritance was observed in one patient with a homozygous R138Q mutation and a de novo NPHS1 mutation. Among 32 patients with two NPHS2 mutations who underwent kidney transplantation, only one developed late recurrence of focal segmental glomerulosclerosis (FSGS). Among 25 patients with sporadic SRNS and post-transplantation recurrence, we detected a heterozygous NPHS2 mutation in one case, and heterozygous variants/polymorphisms in 3 cases.
  
  
  CONCLUSIONS
  Patients with two pathogenic NPHS2 mutations present with early-onset SRNS and very low incidence of post-transplantation recurrence. Heterozygous NPHS2 variants may play a role in atypical cases with mild, late-onset course, and recurrence after transplantation.
authors.affiliation: Inserm U574, Necker-Enfants Malades Hospital, Paris 5 University, Paris, France.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Weber
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.forename: Ernie L
authors.initials: EL
authors.lastname: Esquivel
authors.forename: Vincent
authors.initials: V
authors.lastname: Morinière
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Tête
authors.forename: Christophe
authors.initials: C
authors.lastname: Legendre
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D017668:Age of Onset; D002648:Child; D002675:Child, Preschool; D004351:Drug Resistance; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D016030:Kidney Transplantation; D008565:Membrane Proteins / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000188:drug therapy / Q000235:genetics* / Q000601:surgery*; D010641:Phenotype; D011110:Polymorphism, Genetic; D011507:Proteinuria / Q000188:drug therapy / Q000235:genetics / Q000601:surgery; D012008:Recurrence; D013256:Steroids / Q000627:therapeutic use
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D013256:Steroids