Autosomal Dominant Tubulointerstitial Kidney Disease with Adult Onset due to a Novel Renin Mutation Mapping in the Mature Protein

Abstract

Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a genetically heterogeneous renal disorder leading to progressive loss of renal function. ADTKD- REN is due to rare mutations in renin, all localized in the protein leader peptide and affecting its co-translational insertion in the endoplasmic reticulum (ER). Through exome sequencing in an adult-onset ADTKD family we identified a new renin variant, p.L381P, mapping in the mature protein. To assess its pathogenicity, we combined genetic data, computational and predictive analysis and functional studies. The L381P substitution affects an evolutionary conserved residue, co-segregates with renal disease, is not found in population databases and is predicted to be deleterious by in silico tools and by structural modelling. Expression of the L381P variant leads to its ER retention and induction of the Unfolded Protein Response in cell models and to defective pronephros development in zebrafish. Our work shows that REN mutations outside of renin leader peptide can cause ADTKD and delineates an adult form of ADTKD- REN , a condition which has usually its onset in childhood. This has implications for the molecular diagnosis and the estimated prevalence of the disease and points at ER homeostasis as a common pathway affected in ADTKD- REN , and possibly more generally in ADTKD.

An international cohort study of autosomal dominant tubulointerstitial kidney disease due to mutations identifies distinct clinical subtypes

“…These mutations destabilize renin structure and produce an enzymatically inactive prorenin that is trapped within the ER, similar to the mature REN mutation p.L381P. 11 The localization of the mutated mature renin protein and pathophysiologic changes are very similar to changes found in ADTKD due to U Q12 MOD mutations, and the 2 conditions are quite similar clinically. Better clinical outcomes in the mature group may be due to decreased cellular toxicity of the mature renin mutations and decreased effects on cellular processing of the wild-type renin produced by the normal allele, similar to mutations in the mature insulin peptide found in diabetes mellitus, with onset of symptoms in adulthood.…”

“…Mutations in the genetic region encoding the mature renin peptide had a much milder course compared with patients with mutations in the region encoding the signal peptide or preprorenin, as first noted by Schaeffer et al in their case report of a family with the p.L381P REN mutation. 11 In contrast to patients in the signal and prosegment groups, who often present in childhood, patients in the mature group first present in their 20s with gout or present later in life with unexplained CKD. These patients appear to have normal kidney function early in life.…”

“…[2][3][4][5] ADTKD due to mutations in the REN gene encoding renin (ADTKD-REN) is one of the least common forms of ADTKD, 5 with only 8 families and 28 individuals reported before 2020. [5][6][7][8][9][10][11] Renin is a hormone primarily produced in the kidney that is requisite for tubulogenesis 12 and embryonic kidney formation. 13 The renin-angiotensin system is a key modulator of blood pressure 14 and CKD progression.…”

Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia

“…This results in reduced renin levels in juxtaglomerular cells and exposure to chronic ER stress with detrimental effects on cell survival that ultimately lead to nephron loss. 47 , 48 As previously speculated, SEC61A1 mutations in ADTKD may also specifically impair the translocation of preprorenin, thereby resulting in a clinical phenotype reminiscent of mutations in REN itself. 22 With regard to SCN, transport of NE, which is encoded by the most commonly mutated gene in SCN ( ELANE ), is also shown to be Sec61α1 dependent (see Fig E3 , B ).…”

Glucocorticoid receptor activities in the zebrafish model: a review

“…The transgenic line ia20 was similarly used to monitor GC activity in the first CRISPR/Cas9 zebrafish mutant line developed for Gr (Facchinello et al 2017, Morbiato et al 2019, to study the cross-talk between GC/Gr and the hypoxic transcriptional responses (Vettori et al 2017), to demonstrate how an increase of cortisol induced by stress impairs the regenerative potential of zebrafish heart (Sallin & Jaźwińska 2016) and to visualize the renin effects on pronephros development, as this line shows a robust expression of EGFP in fish kidney (Schaeffer et al 2019).…”