Journal
HUMAN MUTATION
Volume 39, Issue 12, Pages 1854-1860Publisher
WILEY
DOI: 10.1002/humu.23660
Keywords
interallelic interactions; NPHS2; nephrotic syndrome; podocin; dominant; negative; population genetics
Categories
Funding
- Ministry of Human Capacities
- Seventh Framework Programme [2012-305608]
- Hungarian Academy of Sciences [LP2015-11/2015]
- MedinProt Synergy Grant
- National Research, Development and Innovation Office [K109718, K116305, KH125566, EFOP-3.6.3-EKOP-16-2017-00009]
- Agence Nationale de la Recherche [ANR-10-IAHU-01, ANR-12-BSV1-0033.01]
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NPHS2, encoding podocin, is the major gene implicated in steroid-resistant nephrotic syndrome. Its c.686G>A, p.R229Q variant is the first human variant with a mutation-dependent pathogenicity; it is only pathogenic when trans-associated to specific mutations. Secondary to its high allele frequency in the European, South Asian, African, and Latino populations, its benign trans-associations can be accidentally identified in affected patients. Distinguishing pathogenic and benign p.R229Q associations can be challenging. In this paper, we present the currently known pathogenic and benign associations, and show that a rare p.R229Q association can be considered pathogenic if the variant in trans meets the following criteria; it affects the 270-351 residues and alters but does not disrupt the oligomerization, its p.R229Q association is found in a family with slowly progressing focal segmental glomerulosclerosis, but is expected to be rare in the general population (<1:10(6)). We show that >15% of the p.R229Q associations identified so far in patients are benign.
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