Autosomal recessive polycystic kidney disease (ARPKD) is the prototype of the hepato-renal fibrocystic diseases, a subset of the broader ciliopathy disorders. As a severe form of PKD, ARPKD typically manifests in utero with 21% perinatal mortality and progressive loss of kidney function in most post-natal survivors. Congenital hepatic fibrosis is an invariant feature of ARPKD. PKHD1-encoded fibrocystin/polyductin (FPC) is a large 4074 amino acid glycoprotein that likely functions as a receptor molecule and appears to play a key role in maintaining differentiated renal tubular epithelium. The molecular mechanisms by which defects in FPC contribute to ARPKD pathogenesis are just beginning to be elucidated. FPC is a novel protein that likely evolved as vertebrates transitioned from aquatic to semi-terrestrial ecosystems. Full-length human FPC shares a phylogenetically conserved, multi-motif N-terminal region with its ancestral homolog, PKHD1L1, and contains a single-pass transmembrane domain and a novel C-terminal tail that harbors a ciliary targeting motif as well as mitochondrial and nuclear localization sequences. This review synthesizes the full range of recent experimental data about PKHD1/FPC to provide a current functional perspective about this complex protein. We also discuss the clinical relevance of these emerging functional insights for both kidney health and ARPKD pathogenesis.
Gulati et al. (Wed,) studied this question.