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

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

Author information

1
1] First Department of Pediatrics, Semmelweis University, Budapest, Hungary. [2] Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1163, Laboratory of Hereditary Kidney Diseases, Paris, France. [3] Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France.
2
Hungarian Academy of Sciences-Eötvös Loránd University (MTA-ELTE) Protein Modelling Research Group, Budapest, Hungary.
3
1] Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1163, Laboratory of Hereditary Kidney Diseases, Paris, France. [2] Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France.
4
First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
5
1] First Department of Pediatrics, Semmelweis University, Budapest, Hungary. [2] Hungarian Academy of Sciences-Semmelweis University (MTA-SE) Pediatrics and Nephrology Research Group, Budapest, Hungary.
6
1] Hungarian Academy of Sciences-Eötvös Loránd University (MTA-ELTE) Protein Modelling Research Group, Budapest, Hungary. [2] Laboratory of Structural Chemistry and Biology, Eötvös Loránd University, Budapest, Hungary.
7
1] Institut National de la Santé et de la Recherche Médicale (INSERM) Unité Mixte de Recherche (UMR) 1163, Laboratory of Hereditary Kidney Diseases, Paris, France. [2] Paris Descartes University-Sorbonne Paris Cité, Imagine Institute, Paris, France. [3] Assistance Publique-Hôpitaux de Paris, Department of Genetics, Necker Hospital, Paris, France.

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.

PMID:
24509478
DOI:
10.1038/ng.2898
[Indexed for MEDLINE]

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