Molecular and cellular pathogenesis of autosomal recessive polycystic kidney disease. Braz J Med Biol Res

Disciplina de Nefrologia, Departamento de Clínica Médica, Faculdade de Medicina, Universidade de São Paulo, Av. Dr. Arnaldo 455, Sala 3310, 01246-903 São Paulo, SP, Brazil.
Brazilian Journal of Medical and Biological Research (Impact Factor: 1.01). 01/2007; 39(12):1537-48. DOI: 10.1590/S0100-879X2006001200004
Source: PubMed


Autosomal recessive polycystic kidney disease (ARPKD) is an inherited disease characterized by a malformation complex which includes cystically dilated tubules in the kidneys and ductal plate malformation in the liver. The disorder is observed primarily in infancy and childhood, being responsible for significant pediatric morbidity and mortality. All typical forms of ARPKD are caused by mutations in a single gene, PKHD1 (polycystic kidney and hepatic disease 1). This gene has a minimum of 86 exons, assembled into multiple differentially spliced transcripts and has its highest level of expression in kidney, pancreas and liver. Mutational analyses revealed that all patients with both mutations associated with truncation of the longest open reading frame-encoded protein displayed the severe phenotype. This product, polyductin, is a 4,074-amino acid protein expressed in the cytoplasm, plasma membrane and primary apical cilia, a structure that has been implicated in the pathogenesis of different polycystic kidney diseases. In fact, cholangiocytes isolated from an ARPKD rat model develop shorter and dysmorphic cilia, suggesting polyductin to be important for normal ciliary morphology. Polyductin seems also to participate in tubule morphogenesis and cell mitotic orientation along the tubular axis. The recent advances in the understanding of in vitro and animal models of polycystic kidney diseases have shed light on the molecular and cellular mechanisms of cyst formation and progression, allowing the initiation of therapeutic strategy designing and promising perspectives for ARPKD patients. It is notable that vasopressin V2 receptor antagonists can inhibit/halt the renal cystic disease progression in an orthologous rat model of human ARPKD.

Full-text preview

Available from:
  • Source
    • "Patients present with enlarged kidneys and liver, respiratory failure, hypertension, and urinary tract infection (Zerres et al., 1998). Severe cases of the disease present in utero by fetal ultrasound with enlarged and echogenic kidneys, leading to oligohydramnios and possibly to pulmonary hypoplasia (Menezes and Onuchic, 2006). Respiratory insufficiency induced by pulmonary hypoplasia is considered the primary cause of early death in these infants (Guay-Woodford and Bernstein, 2003). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the PKHD1 gene are responsible for autosomal recessive polycystic kidney disease (ARPKD). Using exon scanning by denaturing high-performance liquid chromatography (dHPLC) or bidirectional sequencing of all exons constituting the longest open reading frame, the mutation detection rate reaches approximately 82% and minor lesion mutations include truncating, splice, and missense mutations. The main aim of this study was to screen ARPKD patients in whom only one pathogenic PKHD1 mutation was identified after bidirectional sequencing of the longest open reading frame, for gene copy number alterations by employing multiplex ligation-dependent probe amplification complemented with quantitative real-time polymerase chain reaction. Sixteen ARPKD probands were studied in whom only one clearly pathogenic mutation was previously identified. One patient with a suspected homozygous deletion of the exons 1-37 was also included in this cohort. Three distinct PKHD1 germ-line deletions were identified. Two of these deletions encompassed multiple exons of PKHD1 extending far beyond the 5' and 3' untranslated regions of the gene, and spanning at least 170 and 470 kb, respectively. The third 3.7 kb intragenic deletion affected only exons 20-21 of the PKHD1 gene. Thus, this is the first report presenting analysis of the entire PKHD1 longest open reading frame for gene deletions/duplications in a select cohort of ARPKD patients, in whom previously only one mutation was identified after bidirectional sequencing of the entire longest open reading frame. The data indicate that multiplex ligation-dependent probe amplification is a sensitive and rapid method to identify PKHD1 deletions. Our study demonstrates that dosage analysis will increase the PKHD1 mutation detection rate and should be performed as a complementary assay in patients suspected to have ARPKD in the absence of two clear pathogenic mutations.
    Genetic Testing and Molecular Biomarkers 08/2010; 14(4):505-10. DOI:10.1089/gtmb.2009.0188 · 1.46 Impact Factor
  • Source
    • "Although some embryos have begun to develop dilations in the glomerulus around 2 dpf, this is always accompanied by dilations in the medial tubular region. These cystic dilations appear fusiform in nature, as they are wider at a specific area of the kidney and tapered at either end This is similar architecture to that observed in ARPKD cysts (Menezes and Onuchic, 2006). We first consistently observe glomerular dilations at 2.5 dpf which progress over time (Figure 3, I–L). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Zebrafish are an attractive model for studying the earliest cellular defects occurring during renal cyst formation because its kidney (the pronephros) is simple and genes that cause cystic kidney diseases (CKD) in humans, cause pronephric dilations in zebrafish. By comparing phenotypes in three different mutants, locke, swt and kurly, we find that dilations occur prior to 48 hpf in the medial tubules, a location similar to where cysts form in some mammalian diseases. We demonstrate that the first observable phenotypes associated with dilation include cilia motility and luminal remodeling defects. Importantly, we show that some phenotypes common to human CKD, such as an increased number of cells, are secondary consequences of dilation. Despite having differences in cilia motility, locke, swt and kurly share similar cystic phenotypes, suggesting that they function in a common pathway. To begin to understand the molecular mechanisms involved in cyst formation, we have cloned the swt mutation and find that it encodes a novel leucine rich repeat containing protein (LRRC50), which is thought to function in correct dynein assembly in cilia. Finally, we show that knock-down of polycystic kidney disease 2 (pkd2) specifically causes glomerular cysts and does not affect cilia motility, suggesting multiple mechanisms exist for cyst formation.
    Developmental Biology 03/2008; 314(2):261-75. DOI:10.1016/j.ydbio.2007.11.025 · 3.55 Impact Factor

Show more