Autosomal recessive polycystic kidney disease (ARPKD), usually considered to be a genetically homogeneous disease caused by mutations in PKHD1, has been associated with ciliary dysfunction.
Paxillin coimmunoprecipitation analyses suggested that fibrocystin-1 was a component of the normal focal adhesion complex and that actin and fibrocystin-1 were lost from ARPKD complexes.
Finally, the recent discoveries with the newly identified disease gene PKHD1, which causes autosomal recessive polycystic kidney disease, were also presented at the meeting.
These observations should provide an important platform for determining FPC function and the pathogenesis of ARPKD, with the targeting of mTOR signaling being exploitable as a novel therapy.
Herein, we present a case of ARPKD that was diagnosed at 22 weeks of gestation by ultrasonographic examination and MRI and verified by PKHD1 mutation analysis and array-based genetic deletion analysis.
Mutational analysis of the PKHD1 gene was performed in 11 families with a history of 1 to 6 fetuses or children affected by ARPKD, which either were aborted or died shortly after birth.
To determine whether defects in other human cystoproteins have similar effects, we studied extracellular acidification and glucose metabolism in human embryonic kidney (HEK-293) cell lines with polycystic kidney and hepatic disease 1 ( PKHD1) and polycystic kidney disease (PKD) 2 ( PKD2) truncating defects along multiple sites of truncating mutations found in patients with autosomal recessive and dominant PKDs.
Our aim was to set up the first study of ARPKD patients from the Czech Republic, to determine the composition of their mutations and genotype-phenotype correlations, along with establishment of next-generation sequencing of the PKHD1 gene that could be used for the diagnosis of ARPKD patients.
Autosomal recessive polycystic kidney disease (ARPKD) [MIM 263200] belongs to a group of congenital hepatorenal fibrocystic syndromes and is caused by mutations in the PKHD1 gene encoding the multidomain protein fibrocystin/polyductin (FPC).
In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology.
FPC (fibrocystin or polyductin) is a single transmembrane receptor-like protein, responsible for the human autosomal recessive polycystic kidney disease (ARPKD).
PKHD1/fibrocystin, the defective gene in ARPKD, is expressed in the cilia of bile duct epithelium and leads to abnormalities in the rubric of the ductal plate malformation.
In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.
Fibrocystin is localized to the branching ureteric bud, collecting and biliary ducts, consistent with the disease phenotype, and often absent from ARPKD tissue.
To test this, conditionally immortalized cell lines derived from human fetal ARPKD cyst-lining (pool and clone 5E) cell lines with low levels of fibrocystin/polyductin expression and age-matched normal collecting tubule [human fetal collecting tubule (HFCT) pool and clone 2C] cell lines were grown in culture, loaded with a Ca(2+) indicator dye, and subjected to laminar shear.