These data highlight the importance of a functional REN signal peptide for efficient translocation and corroborate, however, indirectly, our observation of rescuing the impaired REN transport in ADTKD–SEC61A1 cells by a signal peptide substitution or the D2R charge reversal (Figs 5A, S4E, and S8). The gene discussed is SEC61A1; the disease is autosomal dominant medullary cystic kidney disease with or without hyperuricemia.