title: Nephrin mutations can cause childhood-onset steroid-resistant nephrotic syndrome.
abstract: Classically, infants with mutations in NPHS1, which encodes nephrin, present with nephrotic syndrome within the first 3 mo of life (congenital nephrotic syndrome of the Finnish-type), and children with mutations in NPHS2, which encodes podocin, present later with steroid-resistant nephrotic syndrome. Recently, however, NPHS2 mutations have been identified in children with congenital nephrotic syndrome. Whether NPHS1 mutations similarly account for some cases of childhood steroid-resistant nephrotic syndrome is unknown. In this study, 160 patients who belonged to 142 unrelated families and presented with nephrotic syndrome at least 3 mo after birth were screened for NPHS1 variants once mutations in NPHS2 had been excluded. Compound heterozygous NPHS1 mutations were identified in one familial case and nine sporadic cases. Mutations included protein-truncating nonsense and frameshift mutations, as well as splice-site and missense variants. Mutations were classified as "severe" or "mild" using prediction algorithms and functional assays. Most missense variants trafficked normally to the plasma membrane and maintained the ability to form nephrin homodimers and to heterodimerize with NEPH1, suggesting retained function. The presence of at least one "mild" mutation in these patients likely explains the later onset and milder course of disease. These results broaden the spectrum of renal disease related to nephrin mutations.
authors.affiliation: Inserm U574, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Philippe
authors.forename: Fabien
authors.initials: F
authors.lastname: Nevo
authors.forename: Ernie L
authors.initials: EL
authors.lastname: Esquivel
authors.forename: Dalia
authors.initials: D
authors.lastname: Reklaityte
authors.forename: Olivier
authors.initials: O
authors.lastname: Gribouval
authors.forename: Marie-Josèphe
authors.initials: MJ
authors.lastname: Tête
authors.forename: Chantal
authors.initials: C
authors.lastname: Loirat
authors.forename: Jacques
authors.initials: J
authors.lastname: Dantal
authors.forename: Michel
authors.initials: M
authors.lastname: Fischbach
authors.forename: Claire
authors.initials: C
authors.lastname: Pouteil-Noble
authors.forename: Stéphane
authors.initials: S
authors.lastname: Decramer
authors.forename: Martin
authors.initials: M
authors.lastname: Hoehne
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.forename: Marina
authors.initials: M
authors.lastname: Charbit
authors.forename: Patrick
authors.initials: P
authors.lastname: Niaudet
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D017668:Age of Onset; D000465:Algorithms; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D015331:Cohort Studies; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D009404:Nephrotic Syndrome / Q000453:epidemiology* / Q000235:genetics* / Q000473:pathology; D012720:Severity of Illness Index
chemical_list: D008565:Membrane Proteins; C113267:nephrin