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

Tory, Kálmán and Menyhárd, K. Dóra and Woerner, Stephanie and Nevo, Fabien and Gribouval, Olivier and Kerti, Andrea and Stráner, Pál and Arrondel, Christelle and Huynh Cong, Evelyne and Tulassay, Tivadar and Mollet, Géraldine and Perczel, András and Antignac, Corinne (2014) Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nature Genetics, 46. pp. 299-304. ISSN 1061-4036

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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.

Item Type: Article
Subjects: Q Science / természettudomány > QD Chemistry / kémia
Q Science / természettudomány > QP Physiology / élettan
Depositing User: Dóra K. Menyhárd
Date Deposited: 14 Feb 2015 04:39
Last Modified: 08 Sep 2020 15:51

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