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The study of mutations causing the steroid-resistant nephrotic syndrome in children has greatly advanced our understanding of the kidney filtration barrier. In particular, these genetic variants have illuminated the roles of the podocyte, glomerular basement membrane and endothelial cell in glomerular filtration. However, in a significant number of familial and early onset cases, an underlying mutation cannot be identified, indicating that there are likely to be multiple unknown genes with roles in glomerular permeability. We now show how the combination of N-ethyl-N-nitrosourea mutagenesis and next-generation sequencing could be used to identify the range of mutations affecting these pathways. Using this approach, we isolated a novel mouse strain with a viable nephrotic phenotype and used whole-genome sequencing to isolate a causative hypomorphic mutation in Lamb2. This discovery generated a model for one part of the spectrum of human Pierson's syndrome and provides a powerful proof of principle for accelerating gene discovery and improving our understanding of inherited forms of renal disease.

Original publication

DOI

10.1002/path.4308

Type

Journal article

Journal

J Pathol

Publication Date

05/2014

Volume

233

Pages

18 - 26

Keywords

animal model, congenital nephrosis, glomerular basement membrane, kidney glomerulus, mutagenesis, nephrotic syndrome, next-generation sequencing, proteinuria, Abnormalities, Multiple, Animals, DNA Mutational Analysis, Disease Models, Animal, Ethylnitrosourea, Eye Abnormalities, Genetic Association Studies, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing, Kidney Tubules, Laminin, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Mutant Strains, Mutation, Nephrotic Syndrome, Pedigree, Phenotype, Proteinuria, Pupil Disorders