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.
To determine the molecular mechanism of the cystogenesis in ARPKD, we recently generated a mouse model for ARPKD that carries a targeted mutation in the mouse orthologue of human PKHD1.
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.
ARPKD is caused by mutations in the polycystic kidney and hepatic disease 1 (PKHD1) gene, which consists of 86 exons that are variably assembled into a number of alternatively spliced transcripts.
In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology.
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.
Given the limitations of antenatal ultrasound, this is only feasible by molecular genetics that became possible in 1994 when PKHD1, the locus for ARPKD, was mapped to chromosome 6p.
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.