Abstract
Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a genetic disorder with an incidence of ~1:20,000 that manifests in a wide range of renal and liver disease severity in human patients and can lead to perinatal mortality. 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 variation in ARPKD phenotype suggests that in addition to PKHD1 mutations, other genes may play a role, acting as modifiers of disease severity. One such pathway involves non-canonical Wnt/Planar Cell Polarity (PCP) signalling that has been associated with other cystic kidney diseases, but has not been investigated in ARPKD. Analysis of the AtminGpg6 mouse showed kidney, liver and lung abnormalities, suggesting it as a novel mouse tool for the study of ARPKD. Further, modulation of Atmin affected Pkhd1 mRNA levels, altered non-canonical Wnt/PCP signalling and impacted cellular proliferation and adhesion, although Atmin does not bind directly to the C-terminus of Fibrocystin. Differences in ATMIN and VANGL2 expression were observed between normal human paediatric kidneys and age-matched ARPKD kidneys. Significant increases in ATMIN, WNT5A, VANGL2 and SCRIBBLE were seen in human ARPKD versus normal kidneys; no substantial differences were seen in DAAM2 or NPHP2. A striking increase in E-cadherin was also detected in ARPKD kidneys. This work indicates a novel role for non-canonical Wnt/PCP signalling in ARPKD and suggests ATMIN as a modulator of PKHD1.
Highlights
Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder, affecting 1:20,000 to 1:40,000 individuals, mostly foetuses and infants [1] and is a common cause of perinatal death [2]
The initial activation of the pathway (Wnt ligand binding to Fz receptor, Dvl attachment to the membrane) is similar to canonical Wnt signalling, the involvement of core Planar Cell Polarity (PCP) proteins such as the Vangls, results in variable outcomes that impact on cellular signalling processes
Mis-localisation and increased expression of core (VANGL2) and effector (ATMIN) PCP proteins were observed in ARPKD kidneys
Summary
Autosomal Recessive Polycystic Kidney Disease (ARPKD) is a rare hereditary disorder, affecting 1:20,000 to 1:40,000 individuals, mostly foetuses and infants [1] and is a common cause of perinatal death [2]. It manifests as extreme bilateral enlargement of cystic kidneys in utero, associated with hepatic ductal plate abnormalities and pulmonary hypoplasia [3,4]. In those patients who survive the perinatal period, the majority will require renal replacement therapy (dialysis/transplantation) within the first decade [5]. Many different mutations in PKHD1 have been reported throughout the whole gene and the combination of mutations
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