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Trimerization and Genotype-Phenotype Correlation of COL4A5 Mutants in Alport Syndrome.


ABSTRACT: Introduction:Alport syndrome is a hereditary glomerulonephritis that results from the disruption of collagen ?345(IV) heterotrimerization caused by mutation in COL4A3, COL4A4 or COL4A5 genes. Many clinical studies have elucidated the correlation between genotype and phenotype, but there is still much ambiguity and insufficiency. Here, we focused on the ?345(IV) heterotrimerization of ?5(IV) missense mutant as a novel factor to further understand the pathophysiology of Alport syndrome. Methods:We selected 9 ?5(IV) missense mutants with typical glycine substitutions that clinically differed in disease progression. To quantify the trimerization of each mutant, split nanoluciferase-fused ?3/?5 mutants and ?4 were transfected into the cells, and intracellular and secreted heterotrimer were detected by luminescence using an assay that we developed previously. Results:Trimer formation and secretion patterns tended to be similar to the wild type in most of the mutations that did not show proteinuria at a young age. On the other hand, trimer secretion was significantly reduced in all the mutations that showed proteinuria and early onset of renal failure. One of these mutants has low ability of intracellular trimer formation, and the others had the defect of low-level secretion. In addition, the mutant that is assumed to be nonpathogenic has similar trimer formation and secretion pattern as wild-type ?5(IV). Conclusion:The result of cell-based ?345(IV) heterotrimer formation assay was largely correlated with clinical genotype-phenotype. These trimerization assessments provide additional phenotypic considerations and may help to distinguish between pathogenic and nonpathogenic mutations.

SUBMITTER: Kamura M 

PROVIDER: S-EPMC7210609 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

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