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Alport syndrome, a disease of kidney, ear, and eye, is caused by pathogenic variants in the COL4A3, COL4A4, or COL4A5 genes encoding collagen α3α4α5(IV) of basement membranes. Collagen IV chains that are truncated due to nonsense variants/premature termination codons (PTCs) cannot assemble into heterotrimers or incorporate into basement membranes. To investigate the feasibility of PTC readthrough therapy for Alport syndrome, we utilized two NanoLuc reporters in transfected cells: full-length for monitoring translation, and a split version for assessing readthrough product function. Full-length assays of 49 COL4A5 nonsense variants identified eleven as susceptible to PTC readthrough using various readthrough drugs. In split-NanoLuc assays, the predicted missense α5(IV) readthrough products of five nonsense mutations could heterotrimerize with α3(IV) and α4(IV). Readthrough was also observed in kidney cells from an engineered Col4a5 PTC mouse model. These results suggest that readthrough therapy is a feasible approach for a fraction of patients with Alport syndrome.
Pubmed ID: 35243249 RIS Download
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Mus musculus with name C57BL/6J from IMSR.
View all literature mentionsThis unknown targets Rabbit IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets Laminin antibody produced in rabbit
View all literature mentionsThis monoclonal targets vinculin
View all literature mentionsMus musculus with name B6.Cg-Col4a5tm1Yseg/J from IMSR.
View all literature mentionsAllele Detail: Targeted This is a legacy resource.
View all literature mentionsCell line COS-7 is a Transformed cell line with a species of origin Chlorocebus aethiops (Green monkey)
View all literature mentionsCell line HeLa is a Cancer cell line with a species of origin Homo sapiens
View all literature mentionsCell line HEK293T is a Transformed cell line with a species of origin Homo sapiens (Human)
View all literature mentionsCell line HEK293 is a Transformed cell line with a species of origin Homo sapiens (Human)
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