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Genome editing strategies to generate working models of polycystic kidney disease
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Genome editing strategies to generate working models of polycystic kidney disease
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Journal Article
Genome editing strategies to generate working models of polycystic kidney disease
2025
Overview
Autosomal Dominant Polycystic Kidney Disease (ADPKD) is predominantly caused by pathogenic variants in
PKD1
with truncating variants generally associated with more rapid cyst formation. However, it is difficult to predict disease progression, particularly in the case of missense variants. In this context, our aim was to provide a proof of principle that it is possible to generate cellular models carrying specific
PKD1
variants. We generated homozygous (Ex15
−/−
) and heterozygous mutants (Ex15
+/−
) starting from HEK293T cells. Then, the variant c.11614G > A p.(E3872K) was introduced into
PKD1
WT and heterozygous clones, obtaining compound heterozygous (Ex15
+/−
/Ex42
M/M
) cell lines. Functional assays confirmed the pathogenicity of the c.11614G > A variant. Ex15
+/−
/Ex42
M/M
cells behaved similarly to Ex15
−/−
with defective actin polymerization, diminished capacity to complete autophagic flux and reduced mitochondrial respiration. Interestingly, they showed a different behavior in terms of cell-cycle regulation, implying mutation-specific effects. This work provides a starting point for the generation of different ADPKD-related variants using base editors, with the goal of complementing the already available knowledge about genotype-phenotype correlations and potentially reclassifying C3 variants in pathogenic or non-pathogenic.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Actin
/ Autosomal dominant polycystic kidney disease
/ Cloning
/ CRISPR
/ Cysts
/ Genotype-phenotype correlation
/ Humanities and Social Sciences
/ Humans
/ Kidneys
/ M cells
/ Mutation
/ Polycystic Kidney Diseases - genetics
/ Polycystic Kidney, Autosomal Dominant - genetics
/ Polycystic Kidney, Autosomal Dominant - pathology
/ Proteins
/ Science
