Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome

Nat Genet. 2014 Mar;46(3):299-304. doi: 10.1038/ng.2898. Epub 2014 Feb 9.


Monogenic disorders result from defects in a single gene. According to Mendel's laws, these disorders are inherited in either a recessive or dominant fashion. Autosomal-recessive disorders require a disease-causing variant on both alleles, and according to our current understanding, their pathogenicities are not influenced by each other. Here we present an autosomal-recessive disorder, nephrotic syndrome type 2 (MIM 600995), in which the pathogenicity of an NPHS2 allele encoding p.Arg229Gln depends on the trans-associated mutation. We show that, contrary to expectations, this allele leads to a disease phenotype only when it is associated specifically with certain 3' NPHS2 mutations because of an altered heterodimerization and mislocalization of the encoded p.Arg229Gln podocin. The disease-associated 3' mutations exert a dominant-negative effect on p.Arg229Gln podocin but behave as recessive alleles when associated with wild-type podocin. Therefore, the transmission rates for couples carrying the disease-associated mutations and p.Arg229Gln may be substantially different from those expected in autosomal-recessive disorders.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Cell Membrane / metabolism
  • Child
  • Cohort Studies
  • Exons
  • Female
  • Gene Frequency
  • Humans
  • Intracellular Signaling Peptides and Proteins / chemistry
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Male
  • Membrane Proteins / chemistry
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Models, Molecular
  • Mutation*
  • Nephrotic Syndrome / congenital*
  • Nephrotic Syndrome / genetics
  • Nephrotic Syndrome / metabolism
  • Nephrotic Syndrome / pathology
  • Podocytes / metabolism
  • Podocytes / pathology
  • Protein Multimerization
  • Protein Structure, Quaternary


  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NPHS2 protein

Supplementary concepts

  • Nephrotic syndrome, idiopathic, steroid-resistant