There have been few clinical or scientific reports of autosomal dominant tubulointerstitial kidney disease due to REN mutations (ADTKD-REN), limiting characterization. To further study this, we formed an international cohort characterizing 111 individuals from 30 families with both clinical and laboratory findings. Sixty-nine individuals had a REN mutation in the signal peptide region (signal group), 27 in the prosegment (prosegment group), and 15 in the mature renin peptide (mature group). Signal group patients were most severely affected, presenting at a mean age of 19.7 years, with the prosegment group presenting at 22.4 years, and the mature group at 37 years. Anemia was present in childhood in 91% in the signal group, 69% prosegment, and none of the mature group. REN signal peptide mutations reduced hydrophobicity of the signal peptide, which is necessary for recognition and translocation across the endoplasmic reticulum, leading to aberrant delivery of preprorenin into the cytoplasm. REN mutations in the prosegment led to deposition of prorenin and renin in the endoplasmic reticulum-Golgi intermediate compartment and decreased prorenin secretion. Mutations in mature renin led to deposition of the mutant prorenin in the endoplasmic reticulum, similar to patients with ADTKD-UMOD, with a rate of progression to end stage kidney disease (63.6 years) that was significantly slower vs. the signal (53.1 years) and prosegment groups (50.8 years) (significant hazard ratio 0.367). Thus, clinical and laboratory studies revealed subtypes of ADTKD-REN that are pathophysiologically, diagnostically, and clinically distinct.

1st Department of Pediatrics Semmelweis University Budapest Hungary

AP HP CIC BT 504 Créteil France

AP HP Equipe 21 INSERM U 955 Créteil France

Center of Excellence in Biobanking and Biomedical Research Molecular Medicine Research Center University of Cyprus Nicosia Cyprus

Department of Biochemistry University of Cambridge Cambridge UK

Department of Experimental Diagnostic and Specialty Medicine Nephrology Dialysis and Renal Transplant Unit S Orsola Hospital University of Bologna Bologna Italy

Department of General Pediatrics Adolescent Medicine and Neonatology Medical Center Faculty of Medicine Universitätsklinikum Freiburg Freiburg Germany

Department of Medicine Division of Nephrology University of Arizona Health Sciences Center Tucson Arizona USA

Department of Nephrology and Renal Transplantation University Hospitals Leuven Leuven Belgium; Laboratory of Nephrology Department of Microbiology and Immunology Katholieke Universiteit Leuven Leuven Belgium

Department of Nephrology Evangelismos Private Hospital Pafos Cyprus

Department of Nephrology‒Transplantation Necker Hospital APHP Paris France; Paris Descartes University Sorbonne Paris Cité Paris France; Département Biologie cellulaire INSERM U1151 Institut Necker Enfants Malades Paris France

Department of Pediatric Nephrology Medical University Wrocław Poland

Division of Nephrology and Dialysis Department of Medical and Surgical Specialties Radiological Sciences and Public Health University of Brescia and Montichiari Hospital Brescia Italy

Division of Nephrology Department of Medicine Duke University School of Medicine Durham North Carolina USA; Duke Clinical Research Institute Durham North Carolina USA

Division of Nephrology Department of Pediatrics New York University School of Medicine New York New York USA

Division of Nephrology Department of Pediatrics Seattle Children's Hospital University of Washington Seattle Washington USA

Division of Nephrology Department of Pediatrics University of Florida Gainesville Florida USA

Division of Nephrology Indiana University School of Medicine Indianapolis Indiana USA

Division of Nephrology Ospedale Sant'Orsola‒Malpighi Bologna Italy

Exeter Kidney Unit Royal Devon and Exeter NHS Foundation Trust Exeter Devon UK

Institute of Pathophysiology 1st Faculty of Medicine Charles University Prague Czech Republic

Kidney Genetics Group Academic Nephrology Unit Department of Infection Immunity and Cardiovascular Disease University of Sheffield Medical School Sheffield UK

Laboratory of Human Molecular Genetics Faculty of Medicine University of Sfax Sfax Tunisia

Laboratory of Human Molecular Genetics Faculty of Medicine University of Sfax Sfax Tunisia; Medical Genetics Department of Hedi Chaker Hospital Sfax Tunisia

Laboratory of Molecular and Cellular Immunology Hirszfeld Institute of Immunology and Experimental Therapy Polish Academy of Sciences Wrocław Poland

Medical Genetics Unit Policlinico S Orsola Malpighi Bologna Italy

Molecular Genetics of Renal Disorders Division of Genetics and Cell Biology IRCCS San Raffaele Scientific Institute Milan Italy

MTA SE Lendület Nephrogenetic Laboratory Semmelweis University Budapest Hungary; 1st Department of Pediatrics Semmelweis University Budapest Hungary

Nephrology Division University of Montreal Hospital Centre Hopital Saint Luc Montréal Québec Canada

Pediatric Nephrology Centre Hospitalier Universitaire de Toulouse Toulouse France

Pediatric Nephrology University of Texas Southwestern Medical Center Dallas Texas USA

Pediatrics Nephrology Marshfield Medical Center Marshfield Wisconsin USA

Renal Services The Newcastle Hospitals NHS Foundation Trust Newcastle upon Tyne UK; Translational and Clinical Research Institute Faculty of Medical Sciences Newcastle University Newcastle upon Tyne UK; NIHR Newcastle Biomedical Research Centre Newcastle University Newcastle upon Tyne UK

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

Research Unit of Rare Diseases Department of Pediatric and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University Prague Czech Republic; Section on Nephrology Wake Forest School of Medicine Winston Salem North Carolina USA

Section on Nephrology Wake Forest School of Medicine Winston Salem North Carolina USA

Service de Néphrologie‒Transplantation Hôpital de Bicêtre Le Kremlin Bicêtre France

Sorbonne Université Urgences Néphrologiques et Transplantation Rénale Assistance Publique Hôpitaux de Paris Hôpital Tenon Paris France

University of Cologne Faculty of Medicine and University Hospital Cologne Institute of Human Genetics Cologne Germany; University of Cologne Faculty of Medicine and University Hospital Cologne Center for Molecular Medicine Cologne Cologne Germany

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Kidney Int. 2020 Dec;98(6):1397-1400. doi: 10.1016/j.kint.2020.08.013. PubMed

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Devuyst O, Olinger E, Weber S, et al. Autosomal dominant tubulointerstitial kidney disease. Nat Rev Dis Primers. 2019;5:60. PubMed

Hart TC, Gorry MC, Hart PS, et al. Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy. J Med Genet. 2002;39:882–892. PubMed PMC

Kirby A, Gnirke A, Jaffe DB, et al. Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing. Nat Genet. 2013;45:288–393. PubMed PMC

Bolar NA, Golzio C, Zivna M, et al. Heterozygous Loss-of-Function SEC61A1 Mutations Cause Autosomal-Dominant Tubulo-Interstitial and Glomerulocystic Kidney Disease with Anemia. Am J Hum Genet. 2016;99:174–187. PubMed PMC

Zivna M, Hulkova H, Marignon M, et al. Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and CKD. Am J Human Genet. 2009;85:204–213. PubMed PMC

Bleyer AJ, Zivna M, Hulkova H, et al. Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone. Clin Nephrol. 2010;74:411–422. PubMed PMC

Beck BB, Trachtman H, Gitman M, et al. Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD. Am J Kidney Dis. 2011;58:821–825. PubMed PMC

Clissold RL, Clarke HC, Spasic-Boskovic O, et al. Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report. BMC Nephrol. 2017;18:234. PubMed PMC

Petrijan T, Menih M. Discovery of a Novel Mutation in the REN Gene in Patient With Chronic Progressive Kidney Disease of Unknown Etiology Presenting With Acute Spontaneous Carotid Artery Dissection. J Stroke Cerebrovasc Dis. 2019;28:104302. PubMed

Abdelwahed M, Chaabouni Y, Michel-Calemard L, et al. A novel disease-causing mutation in the Renin gene in a Tunisian family with autosomal dominant tubulointerstitial kidney disease. Int J Biochem Cell Biol. 2019;117:105625. PubMed

Schaeffer C, Izzi C, Vettori A, et al. Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein. Sci Rep. 2019;9:11601. PubMed PMC

Gribouval O, Gonzales M, Neuhaus T, et al. Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet. 2005;37:964–968. PubMed

Gomez RA, Sequiera-Lopez MLS. Renin cells in homeostasis, regeneration and immune defence mechanisms. Nat Rev Nephrol. 2018;14:231–245. PubMed PMC

Pugliese NR, Masi S, Taddei S. The renin-angiotensin-aldosterone system: a crossroad from arterial hypertension to heart failure. Heart Fail Rev. 2020;25:31–42. PubMed

Sparks MA, Crowley SD, Gurley SB, Mirotsou M, Coffman TM. Classical Renin-Angiotensis system in kidney physiology. Compr Physiol. 2014;4:1201–1228. PubMed PMC

Imai T, Miyazaki H, Hirose S, et al. Cloning and sequence analysis of cDNA for human renin precursor. Proc Natl Acad Sci USA. 1983;80:7405–7409. PubMed PMC

Schweda F, Friis U, Wagner C, et al. Renin release. Physiology (Bethesda). 2007;22:310–319. PubMed

Sagnella GA. Why is plasma renin activity lower in populations of African origin? J Hum Hypertens. 2001;15:17–25. PubMed

Petersen TN, Brunak S, von Heijne G, Nielsen H. SignalP 4.0: discriminating signal peptides from transmembrane regions. Nat Methods. 2011;8:785–786. PubMed

Jagadeesh KA, Wenger AM, Berger MJ, et al. M-CAP eliminates a majority of variants of uncertain significance in clinical exomes at high sensitivity. Nat Genet. 2016;48:1581–1586. PubMed

Nagahama M, Nakayama K, Hori H, Murakami K. Expression of a deletion mutant of the prosegment of human prorenin in Chinese hamster ovary cells. FEBS Lett. 1989;259:202–204. PubMed

Nakayama K, Nagahama M, Kim WS, et al. Prorenin is sorted into the regulated secretory pathway independent of its processing to renin in mouse pituitary AtT-20 cells. FEBS Lett. 1989;257:89–92. PubMed

Mercure C, Thibault G, Lussier-Cacan S, et al. Molecular analysis of human prorenin prosegment variants in vitro and in vivo. J Biol Chem. 1995;270:16355–16359. PubMed

Guo H, Xiong Y, Witkowski P, et al. Inefficient translocation of preproinsulin contributes to pancreatic beta cell failure and late-onset diabetes. J Biol Chem. 2014;289:16290–16302. PubMed PMC

Liu M, Lara-Lemus R, Shan SO, et al. Impaired cleavage of preproinsulin signal peptide linked to autosomal-dominant diabetes. Diabetes. 2012;61:828–837. PubMed PMC

Arnold A, Horst SA, Gardella TJ, et al. Mutation of the signal peptide-encoding region of the preproparathyroid hormone gene in familial isolated hypoparathyroidism. J Clin Invest. 1990;86:1084–1087. PubMed PMC

Hussain S, Mohd Ali J, Jalaludin MY, Harun F. Permanent neonatal diabetes due to a novel insulin signal peptide mutation. Pediatr Diabetes. 2013;14:299–303. PubMed PMC

Demidyuk IV, Shubin AV, Gasanov EV, Kostrov SV. Propeptides as modulators of functional activity of proteases. Biomol Concepts. 2010;1:305–322. PubMed

Weiss MA. Diabetes mellitus due to the toxic misfolding of proinsulin variants. FEBS Lett. 2013;587:1942–1950. PubMed PMC

Bentley AK, Rees DJ, Rizza C, Brownlee GG. Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position -4. Cell. 1986;45:343–348. PubMed

Saraste J, Marie M. Intermediate compartment (IC): from pre-Golgi vacuoles to a semi-autonomous membrane system. Histochem Cell Biol. 2018;150:407–430. PubMed PMC

Liu M, Sun J, Cui J, et al. INS-gene mutations: from genetics and beta cell biology to clinical disease. Mol Aspects Med. 2015;42:3–18. PubMed PMC

Given BD, Mako ME, Tager HS, et al. Diabetes due to secretion of an abnormal insulin. N Engl J Med. 1980;302:129–135. PubMed

Sakura H, Iwamoto Y, Sakamoto Y, et al. Structurally abnormal insulin in a diabetic patient. Characterization of the mutant insulin A3 (Val----Leu) isolated from the pancreas. J Clin Invest. 1986;78:1666–16672. PubMed PMC

Shoelson S, Fickova M, Haneda M, et al. Identification of a mutant human insulin predicted to contain a serine-for-phenylalanine substitution. Proc Natl Acad Sci US . 1983;80:7390–7394. PubMed PMC

Genome Aggregation Database [Available from: https://gnomad.broadinstitute.org/gene/ENSG00000143839?dataset=gnomad_r3.

Pottel H, Hoste L, Dubourg L, et al. An estimated glomerular filtration rate equation for the full age pectrum. Nephrol Dial Transplant. 2016;31:798–806. PubMed PMC

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Lysosomal Storage-Independent Fabry Disease Variants with α-Galactosidase A Misprocessing-Induced ER Stress and the Unfolded Protein Response

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