Atmin modulates Pkhd1 expression and may mediate autosomal recessive polycystic kidney disease (ARPKD) through altered non-canonical Wnt/planar cell polarity (PCP) signalling
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AbstractAutosomal 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.
CitationRichards T., Modarage K., Dean C., McCarthy-Boxer A., Hilton H., Esapa C., Norman J., Wilson P, Goggolidou P. (2018) 'Atmin modulates Pkhd1 expression and may mediate autosomal recessive polycystic kidney disease (ARPKD) through altered non-canonical Wnt/planar cell polarity (PCP) signalling', Biochimica et Biophysica Acta - Molecular Basis of Disease, 1865 (2) https://doi.org/10.1016/j.bbadis.2018.11.003
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
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