Journal
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 13, Issue 8, Pages 1162-1171Publisher
AMER SOC NEPHROLOGY
DOI: 10.2215/CJN.09100817
Keywords
Biopsy; COL4A3 gene; Diabetes Mellitus; Type 2; Diabetic Nephropathies; diabetic nephropathy; Fluorescent Antibody Technique; gene expression; Gene Frequency; Glomerular Basement Membrane; Humans; kidney; Kidney Failure; Chronic; Maturity-onset diabetes of the young; Parents; Phenotype; Protein Interaction Maps; proteinuria; Staining and Labeling; Susceptibility gene; Whole Exome Sequencing
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Funding
- National Natural Science Foundation of China [81670662, 81370823]
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Background and objectives Despite advances in identifying genetic factors of diabetic kidney disease (DKD), much of the heritability remains unexplained. Nine maturity-onset diabetes in young (MODY) probands with kidney biopsy-proven DKD were selected and included in this study. The probands had more severe DKD compared with their parents with MODY, with overt proteinuria or rapid progression to ESKD. We aimed to explore the contribution of the variants in susceptibility genes of DKD to the severity of kidney phenotype between the probands and their parents. Design, setting, participants, & measurements Whole-exome sequencing was performed to identify suspected MODY probands and their families. Known DKD susceptibility genes were reviewed. Variants reported to be associated with DKD, or those with minor allele frequency <0.05 and predicted to be pathogenic, were selected and analyzed. Immunofluorescence staining of COL4 alpha 3 was performed in kidney specimens of patients with DKD with or without R408H and M1209I of COL4A3 variants. Results HNF1B-MODY, CEL-MODY, PAX4-MODY, and WFS1-MODY were diagnosed among nine families. We identified 196 selected variants of 25 DKD susceptibility genes among the participants. Analysis of phenotype between probands and parents, gene function, and protein-protein interaction networks revealed that COL4A3 variants were involved in the progression of DKD. Weak granular staining of COL4 alpha 3 was observed in the glomerular basement membrane of patients with the R408H and M1209I variants, whereas strong consecutive staining was observed in patients without these variants. Moreover, more number of DKD variants were identified in probands than in their parents with MODY. ConclusionsThe genetic effect of more pathogenic variants in various DKD susceptibility genes, especially variants in the COL4A3 gene, partially explained the more severe kidney phenotype in probands with kidney biopsy-proven DKD.
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