title: Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome.
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.
authors: 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.
authors: Kálmán
authors: K
authors: Tory
authors: Hungarian Academy of Sciences-Eötvös Loránd University (MTA-ELTE) Protein Modelling Research Group, Budapest, Hungary.
authors: Dóra K
authors: DK
authors: Menyhárd
authors: 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.
authors: Stéphanie
authors: S
authors: Woerner
authors: 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.
authors: Fabien
authors: F
authors: Nevo
authors: 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.
authors: Olivier
authors: O
authors: Gribouval
authors: First Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors: Andrea
authors: A
authors: Kerti
authors: Hungarian Academy of Sciences-Eötvös Loránd University (MTA-ELTE) Protein Modelling Research Group, Budapest, Hungary.
authors: Pál
authors: P
authors: Stráner
authors: 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.
authors: Christelle
authors: C
authors: Arrondel
authors: 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.
authors: Evelyne
authors: E
authors: Huynh Cong
authors: 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.
authors: Tivadar
authors: T
authors: Tulassay
authors: 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.
authors: Géraldine
authors: G
authors: Mollet
authors: 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.
authors: András
authors: A
authors: Perczel
authors: 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.
authors: Corinne
authors: C
authors: Antignac
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002462:Cell Membrane / Q000378:metabolism; D002648:Child; D015331:Cohort Studies; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D008958:Models, Molecular; D009154:Mutation; D009404:Nephrotic Syndrome / Q000151:congenital* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D050199:Podocytes / Q000378:metabolism / Q000473:pathology; D055503:Protein Multimerization; D020836:Protein Structure, Quaternary
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C407223:NPHS2 protein