RWTH Aachen University
Mutation Database Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)
Department of Human Genetics, RWTH Aachen University, Pauwelsstraße 30, D-52074 Aachen, Germany



General remarks

It has been crucial to catalogue all changes detected in PKHD1 in a locus specific database. Investigators are invited to submit their novel data to this database. These data should be meaningful for clinical practice as well as of relevance for the reader interested in molecular aspects of polycystic kidney disease (PKD). There are also some links and information for ARPKD patients and their parents. Amendments and suggestions are welcome. For more detailed questions please contact us (humangenetik@ukaachen.de).

PKD research group Aachen Overview

Our research group uses a multidisciplinary approach to understand the genetic and cellular basis of polycystic kidney disease (PKD). The PKDs are a group of inherited disorders that result in renal cyst development often leading to end-stage renal disease. The overall aim of these studies is to understand the normal function of the PKD proteins and define the pathobiology associated with mutations so that rational therapies can be developed for these disorders in future years.

There are two major forms of PKD: Autosomal Dominant (ADPKD) and Autosomal Recessive (ARPKD). ADPKD is one of the most common monogenic disorders with a frequency of 1/500-1000. About 5% of all patients requiring renal replacement therapy (kidney transplant or dialysis) are affected by ADPKD. In most cases of ADPKD (~80%), patients carry a mutation in the PKD1 gene on chromosome 16p13, whereas 10-15% harbour a mutation in the PKD2 gene on chromosome 4q21. While ADPKD is usually a disease of adults, about 1-2% of patients display an early manifesting clinical course and may die perinatally.

Early manifesting cases of ADPKD may mimic the autosomal recessive form (ARPKD) that is usually an infantile disease and an important cause of renal- and liver-related morbidity and mortality in children. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable. We and others have recently identified the disease-causing gene on chromosome 6p12. PKHD1 (Polycystic Kidney and Hepatic Disease 1) is a large gene spanning 470 kb of genomic DNA and giving rise to a cDNA of 12.2 kb. A minimum of 86 exons is supposed to be assembled into a variety of alternatively spliced transcripts. The longest continuous open reading frame is predicted to yield a novel 4,074 aa (∼ 450 kDa) multidomain integral membrane protein (polyductin/fibrocystin) of unknown function. Similar to other cystoproteins, polyductin is localized to primary cilia and the basal body.

Our group is primarily involved in the genetic and cellular analysis of ARPKD.

Our research is driven by several key challenging questions, including:

  • Which mechanisms are involved in the development of liver fibrosis in ARPKD?
  • How are the types of changes correlated to the disease presentation and progression?
  • What is the genetic basis of phenotypic variability in seemingly monogenic disease?
  • What are the binding partners and interacting proteins of polyductin?
  • What is the role of polyductin in the primary cilium and how is ARPKD related to other so called ciliopathies as Meckel syndrome, Joubert syndrome or Bardet-Biedl syndrome?

Mutation Database

Autosomal Recessive Polycystic Kidney Disease (ARPKD/PKHD1)

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research on ARPKD

Current research projects

  1. Liver fibrosis in ARPKD
  2. Characterization of the PKHD1 mutation spectrum
  3. Genotype-phenotype correlations
  4. Genetic basis of phenotypic variability among affected siblings
  5. Interaction and binding studies
  6. Identification of further genes for ARPKD

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