title: Genotype/phenotype correlations of NPHS1 and NPHS2 mutations in nephrotic syndrome advocate a functional inter-relationship in glomerular filtration.
abstract: Mutations of the novel renal glomerular genes NPHS1 and NPHS2 encoding nephrin and podocin cause two types of severe nephrotic syndrome presenting in early life, Finnish type congenital nephrotic syndrome (CNF) and a form of autosomal recessive familial focal segmental glomerulosclerosis (SRN1), respectively. To investigate the mechanisms by which mutations might cause glomerular protein leak, we analysed NPHS1/NPHS2 genotype/phenotype relationships in 41 non-Finnish CNF patients, four patients with congenital (onset 0 to 3 months) focal segmental glomerulosclerosis and five patients with possible SRN1 (onset 6 months to 2 years). We clarify the range of NPHS1 mutations in CNF, detecting mutation 'hot-spots' within the NPHS1 coding sequence. In addition, we describe a novel discordant CNF phenotype characterized by variable clinical severity, apparently influenced by gender. Moreover, we provide evidence that CNF may be genetically heterogeneous by detection of NPHS2 mutations in some CNF patients in whom NPHS1 mutations were not found. We confirm an overlap in the NPHS1/NPHS2 mutation spectrum with the characterization of a unique di-genic inheritance of NPHS1 and NPHS2 mutations, which results in a 'tri-allelic' hit and appears to modify the phenotype from CNF to one of congenital focal segmental glomerulosclerosis (FSGS). This may result from an epistatic gene interaction, and provides a rare example of multiple allelic hits being able to modify an autosomal recessive disease phenotype in humans. Our findings provide the first evidence for a functional inter-relationship between NPHS1 and NPHS2 in human nephrotic disease, thus underscoring their critical role in the regulation of glomerular filtration.
authors.affiliation: Molecular Medicine Unit, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK, Paediatric Department, St Luke's Hospital, Guardamangia, Malta. a.koziell@ich.ucl.ac.uk
authors.forename: Ania
authors.initials: A
authors.lastname: Koziell
authors.forename: Victor
authors.initials: V
authors.lastname: Grech
authors.forename: Sagair
authors.initials: S
authors.lastname: Hussain
authors.forename: Gary
authors.initials: G
authors.lastname: Lee
authors.forename: Ulla
authors.initials: U
authors.lastname: Lenkkeri
authors.forename: Karl
authors.initials: K
authors.lastname: Tryggvason
authors.forename: Peter
authors.initials: P
authors.lastname: Scambler
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D005838:Genotype; D005923:Glomerulosclerosis, Focal Segmental / Q000235:genetics; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D007678:Kidney Glomerulus / Q000502:physiology* / Q000648:ultrastructure; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology; D009404:Nephrotic Syndrome / Q000235:genetics*; D010641:Phenotype; D011506:Proteins / Q000235:genetics* / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein; D011506:Proteins; C113267:nephrin