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

K. Tory, Dóra K. Menyhárd, Stéphanie Woerner, Fabien Nevo, Olivier Gribouval, Andrea Kerti, Pál Stráner, Christelle Arrondel, Evelyne Huynh Cong, T. Tulassay, Géraldine Mollet, A. Perczel, Corinne Antignac

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)299-304
Number of pages6
JournalNature Genetics
Volume46
Issue number3
DOIs
Publication statusPublished - 2014

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Nephrotic Syndrome
Alleles
Steroids
Mutation
Virulence
Phenotype
Genes
NPHS2 protein

ASJC Scopus subject areas

  • Genetics

Cite this

Tory, K., Menyhárd, D. K., Woerner, S., Nevo, F., Gribouval, O., Kerti, A., ... Antignac, C. (2014). Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nature Genetics, 46(3), 299-304. https://doi.org/10.1038/ng.2898

Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. / Tory, K.; Menyhárd, Dóra K.; Woerner, Stéphanie; Nevo, Fabien; Gribouval, Olivier; Kerti, Andrea; Stráner, Pál; Arrondel, Christelle; Cong, Evelyne Huynh; Tulassay, T.; Mollet, Géraldine; Perczel, A.; Antignac, Corinne.

In: Nature Genetics, Vol. 46, No. 3, 2014, p. 299-304.

Research output: Contribution to journalArticle

Tory, K, Menyhárd, DK, Woerner, S, Nevo, F, Gribouval, O, Kerti, A, Stráner, P, Arrondel, C, Cong, EH, Tulassay, T, Mollet, G, Perczel, A & Antignac, C 2014, 'Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome', Nature Genetics, vol. 46, no. 3, pp. 299-304. https://doi.org/10.1038/ng.2898
Tory, K. ; Menyhárd, Dóra K. ; Woerner, Stéphanie ; Nevo, Fabien ; Gribouval, Olivier ; Kerti, Andrea ; Stráner, Pál ; Arrondel, Christelle ; Cong, Evelyne Huynh ; Tulassay, T. ; Mollet, Géraldine ; Perczel, A. ; Antignac, Corinne. / Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. In: Nature Genetics. 2014 ; Vol. 46, No. 3. pp. 299-304.
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