The human Sec61 complex is a widely distributed and abundant molecular machine. It resides in the membrane of the endoplasmic reticulum to channel two types of cargo: protein substrates and calcium ions. The SEC61A1 gene encodes for the pore-forming Sec61α subunit of the Sec61 complex. Despite their ubiquitous expression, the idiopathic SEC61A1 missense mutations p.V67G and p.T185A trigger a localized disease pattern diagnosed as autosomal dominant tubulointerstitial kidney disease (ADTKD-SEC61A1). Using cellular disease models for ADTKD-SEC61A1, we identified an impaired protein transport of the renal secretory protein renin and a reduced abundance of regulatory calcium transporters, including SERCA2. Treatment with the molecular chaperone phenylbutyrate reversed the defective protein transport of renin and the imbalanced calcium homeostasis. Signal peptide substitution experiments pointed at targeting sequences as the cause for the substrate-specific impairment of protein transport in the presence of the V67G or T185A mutations. Similarly, dominant mutations in the signal peptide of renin also cause ADTKD and point to impaired transport of this renal hormone as important pathogenic feature for ADTKD-SEC61A1 patients as well.

Center for Bioinformatics Saarland University Saarbrücken Germany

Department of Chemistry University of Nevada Reno NV USA

Department of Medical Biochemistry and Molecular Biology Saarland University Homburg Germany

Experimental and Clinical Pharmacology and Toxicology Pre clinical Center for Molecular Signaling Saarland University Homburg Germany

Research Unit for Rare Diseases Department of Pediatrics and Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic

Section on Nephrology Wake Forest School of Medicine Winston Salem NC USA

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PDB
3J7Q, 3JC2