Disease Genetics: Insights into monogenic disease


Mutation-dependent recessive inheritance of NPHS2-associated steroid-resistant nephrotic syndrome. Nature Genet. 46, 299–304 (2014) ISTOCK Pathogenicity in autosomal recessive disease has been classically characterized by the presence of two copies of a mutant allele, which do not influence each other. Now, Tory et al. reveal that in steroid-resistant nephrotic syndrome (SRNS), the common variant of the podocin-encoding NPHS2 gene, p.Arg229Gln, can be pathogenic depending on the presence of specific 3ʹ mutations in the other NPHS2 allele. Individuals who are homozygous for the p.Arg229Gln polymorphism of NPHS2 do not develop SRNS. By contrast, individuals who carry p.Arg229Gln in addition to a mutation in the other allele of NPHS2 are affected; however, this genotype (denoted as p.[Arg229Gln];[mut]) is associated with a less severe and later disease onset than that of individuals who are carriers of other known disease-causing variants of both alleles. As the p.Arg229Gln variant is present at 15× higher frequency than the cumulative frequency of all other known SRNS-related NPHS2 variants, late-onset disease should be more prevalent than early-onset disease. However, late-onset disease is actually 3.5× less frequent than early-onset disease, which led the authors to ask whether the p.[Arg229Gln];[mut] genotype is disease causing in all carriers. The authors sequenced the NPHS2 gene in 129 unaffected parents of affected children and found that 4.7% of the parents were compound heterozygotes for p.Arg229Gln and a mutant allele. This indicates incomplete penetrance of the p.[Arg229Gln];[mut] genotype, which is a rare characteristic in autosomal recessive disorders. In parallel, the researchers also determined which specific mutations in the other allele of NPHS2 were carried by affected individuals who expressed the p.Arg229Gln variant. In this way, they showed that carboxy-terminal substitutions encoded by the last two exons of NPHS2, together with the p.Arg229Gln variant, are exclusively associated with SRNS. Tory and colleagues also provide a mechanism for their results by showing that correct membrane localization of podocin is abolished when the p.Arg229Gln mutant protein is co-expressed with one of the associated C-terminal mutant proteins. This mislocalization is due to altered dimerization of p.Arg229Gln with the specific C-terminal mutant forms. Conversely, p.Arg229Gln can form functional heterodimers with the wild-type protein with correct subcellular localization, which is consistent with the genetic data. This study has direct implications on genetic counselling for SRNS and potential implications for other monogenic disorders — the authors suggested that it is “very likely that other polymorphisms may become pathogenic in a very similar mutation-dependent fashion”.

DOI: 10.1038/nrg3699

Cite this paper

@article{Lokody2014DiseaseGI, title={Disease Genetics: Insights into monogenic disease}, author={Isabel Lokody}, journal={Nature Reviews Genetics}, year={2014}, volume={15}, pages={218-218} }