Abstract: FR-PO331

PRKCSH as a Genetic Modifier in Early-Onset Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Schönauer, Ria, University Clinic Leipzig, Leipzig, Germany
  • Seidel, Anna, University Clinic Leipzig, Leipzig, Germany
  • Hoepke, Jana, University Clinic Leipzig, Leipzig, Germany
  • Dittrich, Katalin, University Children Hospital, Leipzig, Leipzig, Germany
  • Neuber, Steffen, BIOSCIENTIA, Ingelheim, Germany
  • Bergmann, Carsten, BIOSCIENTIA, Ingelheim, Germany
  • Halbritter, Jan, University Clinic Leipzig, Leipzig, Germany
Background

Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common hereditary renal disorder accounting for up to 10% of end-stage renal disease (ESRD). Germline mutations within the polycystin (PC) encoding genes PKD1 and PKD2 and accumulating somatic mutations continuously reduce the level of functional polycystins, which is a major determinant for cyst formation. Although most of the patients develop ESRD in the second half of life, a high intrafamilial clinical variability suggests that additional factors influence PC-levels in a disease relevant manner. We investigate the role of PRKCSH as a potential modifier in the family of a patient (index) who already developed ADPKD in utero.

Methods

Genomic mutations of the index patient were identified with an NGS-panel containing polycystic kidney and liver disease genes (PKD1, PKD2, SEC63, PRKCSH, GANAB, HNF1B, LRP5, PKHD1). Analysis of cDNA transcribed from blood-derived mRNA was performed by PCR and Sanger sequencing. Functional impact of mutated PRKCSH and its influence on polycystins were characterized in vitro using transiently transfected cell culture systems.

Results

By NGS of a 2-year old male (index patient) with congenital PKD, we identified transheterozygous mutations in PKD1 (c.1723-1G>C) and PRKCSH (c.205G>A) that encodes the β-subunit of the glucosidase II (GlucII) and is involved in the development of polycystic liver disease. The PKD1 mutation was found to affect the splice site donor of intron 8 and thus, the corresponding PC1 protein ([(575-703)mut]PC11-703) is assumed to lose its function due to the lack of its transmembrane domains. Additionally, the PRKCSH variant results in an amino acid exchange at the highly conserved position 69 of GlucIIβ (p.Ala69Thr), which abolishes its interaction with GlucIIα. Since GlucII participates in the maturation of polycystins in the endoplasmatic reticulum, its defect further reduces the level of functional polycystins.

Conclusion

In summary, while heterozygous loss-of-function mutation of PKD1 resulted in adult onset of ADPKD, the presence of an additional deleterious in-trans variant in PRKCSH severely accelerated cystogenesis. Thus, we demonstrate that by interfering with polycystin maturation, PRKCSH plays a role as genetic modifier in ADPKD and contributes to the observed clinical variability.