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- Title
Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome.
- Authors
Tory, Kálmán; Menyhárd, Dóra K; Woerner, Stéphanie; Nevo, Fabien; Gribouval, Olivier; Kerti, Andrea; Stráner, Pál; Arrondel, Christelle; Cong, Evelyne Huynh; Tulassay, Tivadar; Mollet, Géraldine; Perczel, András; Antignac, Corinne
- Abstract
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.
- Subjects
HEREDITY; GENETIC mutation; AUTOSOMAL recessive polycystic kidney; GENETICS; PHENOTYPES
- Publication
Nature Genetics, 2014, Vol 46, Issue 3, p299
- ISSN
1061-4036
- Publication type
Article
- DOI
10.1038/ng.2898