Atmin modulates Pkhd1 expression and may mediate Autosomal Recessive Polycystic Kidney Disease (ARPKD) through altered non-canonical Wnt/Planar Cell Polarity (PCP) signalling.

Autosomal Recessive Polycystic Kidney Disease 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. 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 duanyu37KD 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 Analysis of the Atmin^Gpg6 mouse showed kidney, liver and lung abnormalities, suggesting it as a novel mouse tool for the study of duanyu37KD. 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 duanyu37KD kidneys. Significant increases in ATMIN, WNT5A, VANGL2 and SCRIBBLE were seen in human duanyu37KD versus normal kidneys; no substantial differences were seen in DAAM2 or NPHP2. A striking increase in E-cadherin was also detected in duanyu37KD kidneys. This work indicates a novel role for non-canonical Wnt/PCP signalling in duanyu37KD and suggests ATMIN as a modulator of PKHD1.

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