Clinical InvestigationAn international cohort study of autosomal dominant tubulointerstitial kidney disease due to REN mutations identifies distinct clinical subtypes
Graphical abstract
Section snippets
Results
Of the 111 individuals from 30 families (Table 1, and Supplementary Figures S1 and S2), 69 (62%) individuals had a mutation in the signal peptide, 27 (24%) in the prosegment, and 15 (14%) in the mature renin peptide. A mutation in p.S45N was identified in 1 individual with ADTKD of unknown cause. This mutation did not segregate with disease and was determined to be nonpathogenic; it was included as a control for laboratory investigations. While searching variant databases, we noticed 2
Discussion
In this work we describe distinct clinical and pathophysiologic differences (Figure 10) in signal, prosegment, and mature peptide mutations of the REN gene in a cohort of 111 patients from 30 families with ADTKD-REN.
Patients with mutations in the signal peptide region were the most severely affected. One third of the patients presented before 10 years of age, with 10% having acute kidney injury and 13% presenting with anemia, acidosis, and kidney failure. The mean age of presentation was lower
Methods
This investigation was approved by the institutional review boards of the participating centers and was carried out in accordance with the Declaration of Helsinki.
Disclosure
All the authors declared no competing interests.
Acknowledgments
The authors thank all participating patients and families, and the referring physicians. We also thank Dr. Heike Göbel (Institute of Pathology, University Hospital of Cologne, Cologne, Germany) and Dr. Helmut Hopfer (Institute of Pathology, University Hospital Basel, Basel, Switzerland) for providing renal sections. This study was supported by a grant from the Ministry of Health of the Czech Republic (NV17-29786A) and by institutional programs of Charles University in Prague, Czech Republic
References (37)
- et al.
Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia
Am J Hum Genet
(2016) - et al.
Dominant renin gene mutations associated with early-onset hyperuricemia, anemia, and CKD
Am J Human Genet
(2009) - et al.
Autosomal dominant mutation in the signal peptide of renin in a kindred with anemia, hyperuricemia, and CKD
Am J Kidney Dis
(2011) - et al.
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) - 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) - et al.
Expression of a deletion mutant of the prosegment of human prorenin in Chinese hamster ovary cells
FEBS Lett
(1989) - 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) - et al.
Molecular analysis of human prorenin prosegment variants in vitro and in vivo
J Biol Chem
(1995) - et al.
Inefficient translocation of preproinsulin contributes to pancreatic beta cell failure and late-onset diabetes
J Biol Chem
(2014) Diabetes mellitus due to the toxic misfolding of proinsulin variants
FEBS Lett
(2013)
Defective propeptide processing of blood clotting factor IX caused by mutation of arginine to glutamine at position -4
Cell
INS-gene mutations: from genetics and beta cell biology to clinical disease
Mol Aspects Med
Autosomal dominant tubulointerstitial kidney disease
Nat Rev Dis Primers
Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy
J Med Genet
Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
Nat Genet
Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone
Clin Nephrol
Discovery of a novel dominant mutation in the REN gene after forty years of renal disease: a case report
BMC Nephrol
Autosomal dominant tubulointerstitial kidney disease with adult onset due to a novel renin mutation mapping in the mature protein
Sci Rep
Cited by (24)
Description of a New Simple and Cost-Effective Molecular Testing That Could Simplify MUC1 Variant Detection
2024, Kidney International ReportsBi-allelic REN Mutations and Undetectable Plasma Renin Activity in a Patient With Progressive CKD
2023, Kidney International ReportsAutosomal Dominant Tubulointerstitial Kidney Disease: An Emerging Cause of Genetic CKD
2022, Kidney International ReportsCitation Excerpt :Patients with REN disease-causing variants in the mature peptide showed a milder course of the disease with gout in early adulthood or CKD later in life.62 Differences in the median age at ESRD were also observed among the 3 groups of patients, with patients with pathogenic variants in the signal peptide and prosegment reaching ESRD earlier (57 years and 62 years, respectively) than the patients with pathogenic variants located in the mature protein (68 years).61 Findings suggestive of ADTKD-REN are very early onset of CKD, which can be found at 3 or 4 years of age or even earlier; hypoproliferative anemia beginning early in life (1 year or 3 years) and resolving during adolescence; and hyperuricemia and gout, usually in the second decade of life.
Detecting MUC1 Variants in Patients Clinicopathologically Diagnosed With Having Autosomal Dominant Tubulointerstitial Kidney Disease
2022, Kidney International ReportsCitation Excerpt :Nevertheless, a recent international cohort study on clinical characteristics of 111 ADTKD-REN patients reported that approximately 70% of the patients presented to medical institutions for chronic kidney disease or gout.21 According to this report, childhood anemia was present in 75.8% of the patients but its severity was relatively mild; mean hemoglobin levels were 9.6, 10.1, and 10.5 g/dl for ages <10 years, 10 to <15 years, and 15 to <20 years, respectively.21 Although hypotension was not reported in the article, the severity of hyperkalemia was mild and the mean serum potassium level in patients who were not taking fludrocortisone was 4.8 mEq/l.21 Childhood anemia, hypotension, or hyperkalemia may often be overlooked, and they are not always specific to ADRKD-REN; thus, we did not exclude participants with these findings.
Cystic Diseases of the Kidney
2022, Emery and Rimoin's Principles and Practice of Medical Genetics and Genomics: Hematologic, Renal, and Immunologic DisordersA Rare Kidney Disease To Cure Them All? Towards Mechanism-Based Therapies for Proteinopathies
2021, Trends in Molecular Medicine
see commentary on page 1397