Autosomal-dominant tubulo-interstitial kidney disease (ADTKD) encompasses a group of disorders characterized by renal tubular and interstitial abnormalities, leading to slow progressive loss of kidney function requiring dialysis and kidney transplantation. Mutations in UMOD, MUC1, and REN are responsible for many, but not all, cases of ADTKD. We report on two families with ADTKD and congenital anemia accompanied by either intrauterine growth retardation or neutropenia. Ultrasound and kidney biopsy revealed small dysplastic kidneys with cysts and tubular atrophy with secondary glomerular sclerosis, respectively. Exclusion of known ADTKD genes coupled with linkage analysis, whole-exome sequencing, and targeted re-sequencing identified heterozygous missense variants in SEC61A1-c.553A>G (p.Thr185Ala) and c.200T>G (p.Val67Gly)-both affecting functionally important and conserved residues in SEC61. Both transiently expressed SEC6A1A variants are delocalized to the Golgi, a finding confirmed in a renal biopsy from an affected individual. Suppression or CRISPR-mediated deletions of sec61al2 in zebrafish embryos induced convolution defects of the pronephric tubules but not the pronephric ducts, consistent with the tubular atrophy observed in the affected individuals. Human mRNA encoding either of the two pathogenic alleles failed to rescue this phenotype as opposed to a complete rescue by human wild-type mRNA. Taken together, these findings provide a mechanism by which mutations in SEC61A1 lead to an autosomal-dominant syndromic form of progressive chronic kidney disease. We highlight protein translocation defects across the endoplasmic reticulum membrane, the principal role of the SEC61 complex, as a contributory pathogenic mechanism for ADTKD.

Center for Human Disease Modeling and Departments of Cell Biology and Psychiatry Duke University Durham NC 27710 USA

Center of Medical Genetics Faculty of Medicine and Health Sciences University of Antwerp and Antwerp University Hospital Antwerp 2650 Belgium

Center of Medical Genetics Faculty of Medicine and Health Sciences University of Antwerp and Antwerp University Hospital Antwerp 2650 Belgium; Department of Human Genetics Radboud University Medical Centre 6500 HB Nijmegen the Netherlands

Department of Human Genetics Radboud University Medical Centre 6500 HB Nijmegen the Netherlands

Department of Medicine Division of Renal Diseases and Hypertension University of Minnesota MN 55455 USA

Department of Nephrology Sint Jan Hospital Brugge 8000 Belgium

Department of Nephrology Sint Lucas Hospital Brugge 8310 Belgium

Department of Pathology University Hospital of Ghent Ghent 9000 Belgium

Department of Pediatric Nephrology University Hospital of Ghent Ghent 9000 Belgium

INSERM U983 Paris Cedex 15 France

Institute for Inherited Metabolic Disorders Prague 1st Faculty of Medicine Charles University Prague 120 00 Prague Czech Republic

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic 166 10 Prague Czech Republic

Section on Nephrology Wake Forest School of Medicine Medical Center Blvd Winston Salem NC 27157 USA

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