PKHD1 Research Articles

The molecular structure and function of fibrocystin, the key gene product implicated in autosomal recessive polycystic kidney disease (ARPKD).

Autosomal recessive polycystic kidney disease is an early onset inherited hepatorenal disorder affecting around 1 in 20,000 births with no approved specific therapies. The disease is almost always caused by variations in the polycystic kidney and hepatic disease 1 gene, which encodes fibrocystin (FC), a very large, single-pass transmembrane glycoprotein found in primary cilia, urine and urinary exosomes. By comparison to proteins involved in autosomal dominant PKD, our structural and molecular understanding of FC has lagged far behind such that there are no published experimentally determined structures of any part of the protein. Bioinformatics analyses predict that the ectodomain contains a long chain of immunoglobulin-like plexin-transcription factor domains, a protective antigen 14 domain, a tandem G8-TMEM2 homology region and a sperm protein, enterokinase and agrin domain. Here we review current knowledge on the molecular function of the protein from a structural perspective.

The carboxy-terminus of the human ARPKD protein fibrocystin can control STAT3 signalling by regulating SRC-activation.

Autosomal recessive polycystic kidney disease (ARPKD) is mainly caused by variants in the PKHD1 gene, encoding fibrocystin (FC), a large transmembrane protein of incompletely understood cellular function. Here, we show that a C‐terminal fragment of human FC can suppress a signalling module of the kinase SRC and signal transducer and activator of transcription 3 (STAT3). Consistently, we identified truncating genetic variants specifically affecting the cytoplasmic tail in ARPKD patients, found SRC and the cytoplasmic tail of fibrocystin in a joint dynamic protein complex and observed increased activation of both SRC and STAT3 in cyst‐lining renal epithelial cells of ARPKD patients.

SVEP1, PKHD1, and P53 expression in primary liver cancer and its clinical significance

SVEP1, PKHD1, and P53 expression in primary liver cancer and its clinical significance

Application of targeted exome capture in identifying genetic mutations in ciliopathies

Objective To develop an approach based on next-generation sequencing to determine the genetic defects in ciliopathies precisely and effectively. Methods Six suspected cases of ciliopathies were enrolled from July 2009 to December 2014 in the PLA General Hospital. Cord blood or tissue of the probands and peripheral blood samples of all the parents were collected for karyotyping analysis. Tissue or blood DNA from the six cases was scanned on 113 kinds of genes related to ciliopathies using targeted exome capture with high throughput sequencing. Mutations detected from the related genes were confirmed by direct Sanger sequencing reactions. Results Karyotype was normal in all the six cases. Pathogenic genes were found in five cases, including PKHD1 mutation in two cases (case one with c.6091delG and c.865delC, and case two with c.11042T>G and c.5137G>T); TCTN2 mutation in one case (c.343G>T and c.1540C>T) and CEP290 mutation in one case (c.7328_7332del and c.4897C>T). All were compound heterozygous mutations. TMEM67 mutation was found in one case (c.1645C>T), which was homozygous mutation. First-generation sequencing confirmed that these mutations originated from their parents. No definite pathogenic courses were found in one case (case six). Conclusions Targeted exome capture with high throughput sequencing is a new approach to find pathogenic gene mutations in ciliopathies. The methodology provides a reliable strategy for routine gene diagnosis and genetic counseling on ciliopathies. Key words: Polycystic kidney, autosomal recessive; Ciliary motility disorders; Encephalocele; Abnormalities, multiple; Exons; High-throughput nucleotide sequencing

Polycystic kidney disease: genes, proteins, animal models, disease mechanisms and therapeutic opportunities

An increased understanding of the genetic, molecular and cellular mechanisms responsible for the development of polycystic kidney disease has laid out the foundation for the development of rational therapies. Many animal models where these therapies can be tested are currently available. This review summarizes the rationale for these treatments, the results of preclinical trials and the prospects for clinical trials, some already in early phases of implementation.