title: Novel NPHS2 variant in patients with familial steroid-resistant nephrotic syndrome with early onset, slow progression and dominant inheritance pattern.
abstract: BACKGROUND
  Steroid-resistant nephrotic syndrome (SRNS) is a common cause of end-stage renal disease in children but also occurs as an adult-onset condition. In a subset of SRNS patients, pathogenic variants are found in genes coding for podocyte foot process proteins. The aim of this study was to define the role of pathogenic variants in Finnish patients with familial and sporadic SRNS.
  
  
  METHODS
  We analyzed SRNS-related genes NPHS1, NPHS2, NEPH1, ACTN4, TRPC6, INF2, WT1, CD2AP, LAMB2, and PLCE1 for disease-causing variants using direct sequencing of exons and intron/exon boundaries in all members of a family with dominant SRNS with early onset and slow progression to end-stage renal disease. We carried out a whole genome sequencing in two affected and two healthy family members. The function of found podocin variant was studied using co-immunoprecipitation and immunohistochemistry. Podocyte gene sequences were analyzed in a cohort of Finnish non-familial SRNS patients.
  
  
  RESULTS
  A heterozygous de novo deletion, c.988_989delCT in NPHS2, was found in all affected family members and in none of their healthy relatives, non-familial patients or controls. No other SRNS-related gene variant, coding or non-coding co-segregated with the disease phenotype in the family. While the truncated podocin remained able to bind nephrin, the expression of nephrin was fragmented and podocin expression reduced. The gene analysis of the non-familial SRNS patients revealed few variants.
  
  
  CONCLUSIONS
  The role of podocin variants in nephrotic syndrome may be more varied than previously thought.
authors: Children's Hospital, University of Helsinki and Helsinki University Hospital, Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland. maija.suvanto@helsinki.fi.
authors: Maija
authors: http://orcid.org/0000-0001-9271-7778
authors: M
authors: Suvanto
authors: Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institute, Stockholm, Sweden.
authors: Jaakko
authors: J
authors: Patrakka
authors: Children's Hospital, University of Helsinki and Helsinki University Hospital, Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.|Department of Medical Biochemistry and Biophysics, Division of Matrix Biology, Karolinska Institute, Stockholm, Sweden.
authors: Timo
authors: T
authors: Jahnukainen
authors: Department of Pediatrics, District Hospital of Pietarsaari, Pietarsaari, Finland.
authors: Pia-Maria
authors: PM
authors: Sjöström
authors: Department of Pediatrics, University Hospital of Oulu, Oulu, Finland.
authors: Matti
authors: M
authors: Nuutinen
authors: Department of Pediatrics, Kuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors: Pekka
authors: P
authors: Arikoski
authors: Department of Pediatrics, University Hospital of Turku, Turku, Finland.
authors: Janne
authors: J
authors: Kataja
authors: Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland.
authors: Marjo
authors: M
authors: Kestilä
authors: Children's Hospital, University of Helsinki and Helsinki University Hospital, Biomedicum 2U, Tukholmankatu 8, 00290, Helsinki, Finland.
authors: Hannu
authors: H
authors: Jalanko
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D018450:Disease Progression; D004351:Drug Resistance / Q000235:genetics*; D005387:Finland; D005799:Genes, Dominant; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D040941:Heredity; D006579:Heterozygote; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D007676:Kidney Failure, Chronic / Q000175:diagnosis / Q000235:genetics / Q000628:therapy; D016030:Kidney Transplantation; D008565:Membrane Proteins / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D010375:Pedigree; D010641:Phenotype; D006435:Renal Dialysis; D017384:Sequence Deletion; D013256:Steroids / Q000627:therapeutic use*; D013997:Time Factors; D000073336:Whole Genome Sequencing; D055815:Young Adult
chemical_list: D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D013256:Steroids
keywords: Glomerulus; Podocin; Podocyte