期刊
NATURE GENETICS
卷 46, 期 3, 页码 299-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2898
关键词
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资金
- Fondation pour la Recherche Medicale [DMP 2010-11-20-386]
- Agence Nationale de la Recherche (GenPod) [ANR-12-BSV1-0033.01]
- 'Investments for the Future' program [ANR-10-IAHU-01]
- European Community [2012-305608 (Eurenomics)]
- Fondation Association pour la Recherche sur le Cancer (ARC) [TAMOP-4.2.1/B-09/1/KMR-2010-0001]
- OTKA [84087/2010]
- Hungarian Scientific Research Fund (OTKA) [NK101072, K109718, PD101095]
- Bolyai Janos research fellowship of the Hungarian Academy of Sciences
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV1-0033] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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