Kidney Week

Abstract: SA-PO607

Identification of a New Mutation Mapping in the Renin Mature Protein Associated with Autosomal Dominant Tubulo-Interstitial Kidney Disease

Session Information

• Noncystic Mendelian Diseases
  November 04, 2017 | Location: Hall H, Morial Convention Center
  Abstract Time: 10:00 AM - 10:00 AM

Category: Genetic Diseases of the Kidney

• 801 Cystic Kidney Diseases

Authors

• Schaeffer, Celine, San Raffaele Scientific Institute, MILAN, Italy

Celine Schaeffer,

• Izzi, Claudia, Montichiari Hospital, ASST, Montichiari (Brescia), Italy

Claudia Izzi,

• Savoldi, Gianfranco, Montichiari Hospital, ASST, Montichiari (Brescia), Italy

Gianfranco Savoldi,

• Pasqualetto, Elena, San Raffaele Scientific Institute, MILAN, Italy

Elena Pasqualetto,

• Caridi, Gianluca, Gaslini Institute, Genova, Italy

Gianluca Caridi,

• Amoroso, Antonio, University of Torino , Torino, Italy

Antonio Amoroso,

• Rampoldi, Luca, San Raffaele Scientific Institute, MILAN, Italy

Luca Rampoldi,

• Scolari, Francesco, Montichiari Hospital, ASST, Montichiari (Brescia), Italy

Francesco Scolari,

Background

Autosomal dominant tubulo-interstitial kidney diseases (ADTKD) is a renal disorder characterised by interstitial fibrosis, tubular atrophy and dilation, and thickening and lamellation of tubular basal membranes. Known responsible genes are UMOD (uromodulin), MUC1 (mucin 1), HNF1B (HNF1beta), REN (renin) and SEC61A1 (Sec 61 translocon alpha 1 subunit). ADTKD-REN is usually characterised by early onset, anaemia during childhood, hyperkaelemia and mild hypotension. All ADTKD mutations in renin so far reported are localised in the leader peptide of the protein (aa 1-23; exon 1), affecting its co-translational insertion in the endoplasmic reticulum (ER).

Methods

Whole exome sequencing was performed on 3 sibs (2 affected and 1 healthy) of a pedigree with suspected ADTKD of unknown origin that tested negative for UMOD, HNF1B and REN (exon1). A variant was found in REN (exon 10) and confirmed by Sanger sequencing. The effect of such variant was studied by expression in cell lines.

Results

We identified a unique REN mutation (p.L381P) that is associated with ADTKD. This variant co-segregates with renal disease following an autosomal dominant way on inheritance. It was found in all tested affected individuals (3) and absent in healthy subject (1). The p.L381P variant is not found in sequence databases from disease-specific and population genetic studies (ExAC, gnomAD). Interestingly this variant maps in mature renin and is predicted to be damaging (Polyphen, SIFT, SDM). Functional studies in HEK293 and AtT20 cell lines showed that L381P renin is fully retained in the ER and it is absent from the culturing medium. This effect is likely due to mutant protein misfolding. ER retention induces ER stress. Co-expression of mutant protein with wild type renin does not interfere with wild type protein trafficking and secretion.

Conclusion

These results suggest that the spectrum of REN mutations associated with ADTKD is broader and that screening of the REN gene in patients compatible with ADTKD diagnosis should not be limited to exon 1. Interestingly, the possible mechanism of pathogenesis associated with the p.L381P mutation, i.e. ER stress and reduced secretion, is likely similar to the one proposed for already described mutations in the leader peptide.