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Comprehensive genomic analysis of PKHD1 mutations in ARPKD cohorts
  1. A M Sharp1,
  2. L M Messiaen2,
  3. G Page3,
  4. C Antignac4,
  5. M-C Gubler5,
  6. L F Onuchic6,
  7. S Somlo7,
  8. G G Germino8,
  9. L M Guay-Woodford1
  1. 1Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
  2. 2Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, USA
  3. 3Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL, USA
  4. 4Department of Genetics, Hopital Necker-Enfants Malades, Paris, France
  5. 5INSERM U574, Hopital Necker-Enfants Malades, Paris, France
  6. 6Department of Medicine, University of São Paulo School of Medicine, São Paulo, Brazil
  7. 7Departments of Internal Medicine and Genetics, Yale University School of Medicine, New Haven, CT, USA
  8. 8Departments of Medicine and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  1. Correspondence to:
 Dr Lisa M Guay-Woodford
 Division of Genetic and Translational Medicine, University of Alabama at Birmingham, 740 Kaul Human Genetics Building, 720 20th Street South, Birmingham, AL, USA;

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Autosomal recessive polycystic kidney disease (ARPKD; MIM 263200) is an important childhood nephropathy, occurring in 1 in 20 000 live births.1 The clinical phenotype is dominated by dilatation of the renal collecting ducts, biliary dysgenesis, and portal tract fibrosis. Affected children often present in utero with enlarged, echogenic kidneys, as well as oligohydramnios secondary to poor urine output. Approximately 30% of affected neonates die shortly after birth as a result of severe pulmonary hypoplasia and secondary respiratory insufficiency. Those who survive the perinatal period express widely variable disease phenotypes with systemic hypertension, renal insufficiency, and portal hypertension due to portal tract fibrosis as the most common clinical features.2

Linkage analysis indicates that mutations in a single locus on chromosome 6p12 are responsible for all typical forms of ARPKD.3,4 Two groups working independently have identified PKHD1 (MIM 606702) as the locus responsible for ARPKD and have demonstrated that this novel gene is among the largest in the human genome, extending over at least 470 kb and including a minimum of 86 exons.5,6 Both PKHD1 and its mouse orthologue (Pkhd1) encode a complex and extensive array of splice variants, with most abundant transcriptional expression in fetal and adult kidney and weaker expression in other tissues including liver and pancreas.5,7 The longest PKHD1 transcript includes 67 exons with an open reading frame (ORF) composed of 66 exons that encode a 4074 amino acid protein, polyductin/fibrocystin.5,6 The full length protein is predicted to have several immunoglobulin-like, plexin, transcription factor (IPT) domains and multiple parallel beta-helix 1 (PbH1) repeats in its approximately 3860 amino acid extracellular amino terminus; a single transmembrane (TM) spanning domain; and a short, cytoplasmic carboxyl terminus with potential phosphorylation sites. Alternatively spliced transcripts are predicted to fall into two broad groups. …

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  • These investigations were supported by the National Institutes of Health (GGG), the Polycystic Kidney Disease Foundation (LG-W), and a Clinical Scientist Award in Translational Research from the Burroughs-Wellcome Foundation (LG-W).

  • Competing interests: none declared