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Kidney Week

Abstract: TH-PO570

The Role of ATMIN in Autosomal Recessive Polycystic Kidney Disease (ARPKD)

Session Information

Category: Genetic Diseases of the Kidney

  • 801 Cystic Kidney Diseases

Authors

  • Goggolidou, Paraskevi, University of Wolverhampton, Wolverhampton, United Kingdom
  • Norman, Jill T, UCL Medical Campus, Royal Free Hospital, London, United Kingdom
  • Wilson, Patricia D., UCL Medical Campus, Royal Free Hospital, London, United Kingdom
Background

ARPKD is a genetic disorder with an incidence of ~1:20,000 that can lead to perinatal mortality. In the ~60% of ARPKD patients who survive the neonatal period, there is a range of disease severity, however, little is known about the genetic mechanisms that regulate ARPKD. ARPKD is caused by mutations in PKHD1 which encodes the large membrane protein, fibrocystin, required for normal branching morphogenesis of the ureteric bud during embryonic renal development. The range of disease severity observed in ARPKD suggests that besides PKHD1 that when mutated causes ARPKD, other genes might also play a role in ARPKD, acting as modifiers of disease severity. Our previous work on ATMIN has shown that it plays a role in kidney morphogenesis by modulating Planar Cell Polarity (PCP) signalling.

Methods

Quantitative Real-time PCR and immunohistochemistry was employed in age-matched normal and ARPKD human kidneys, to investigate causal (fibrocystin) and PCP (Daam2, ATMIN, NPHP2/Inversin) effects. Atmin and Pkhd1 siRNA-mediated knockdowns and Atmin-Green Fluorescent Protein (GFP) overexpression studies were conducted in mouse inner medullary collecting duct (IMCD3) cells, to study the mechanistic relationship between Atmin and Fibrocystin.

Results

A 2-fold increase in ATMIN was observed in human ARPKD vs normal kidneys; no significant differences were seen in DAAM2 or NPHP2. In normal human kidneys ATMIN, Inversin and Fibrocystin were expressed in ureteric bud-derived collecting tubules, whereas in age-matched ARPKD tissue, strong ATMIN and Inversin expression was observed in cyst-lining epithelia. An association was observed between Atmin and Fibrocystin in IMCD3 cells, as siRNA-mediated knockdown of Atmin dramatically reduced Pkhd1 expression; siRNA-mediated knockdown of Pkhd1 almost completely depleted Atmin expression. Atmin-GFP overexpression in IMCD3 cells caused a 6-fold increase in Pkhd1 expression. No significant change in other Wnt signalling (Dvl1, Nphp2) or polycystin (Pkd1, Pkd2) levels was observed. We are currently investigating whether ATMIN and Fibrocystin are in the same protein complex, with preliminary data in normal mouse kidney suggesting that this is the case.

Conclusion

This work suggests that ATMIN interacts with Fibrocystin, proposing ATMIN as a modifier of ARPKD that could in the
long term be used as a biomarker of ARPKD severity and progression.