Algorithm for efficient PKHD1 mutation screening in autosomal recessive polycystic kidney disease (ARPKD).

Abstract

Autosomal recessive polycystic kidney disease (ARPKD) is an important cause of childhood renal- and liver-related morbidity and mortality with variable disease expression. While most cases manifest peri-/neonatally with a high mortality rate in the first month of life, others survive to adulthood. ARPKD is caused by mutations in the Polycystic Kidney and Hepatic Disease 1 (PKHD1) gene on chromosome 6p12. PKHD1 is an exceptionally large gene (470 kb) with a longest open reading frame transcript of 67 exons predicted to encode a 4,074-amino acid (aa) (447 kDa) multidomain integral membrane protein (fibrocystin/polyductin) of unknown function. Recent DHPLC-based mutational studies have reported detection rates of about 80% and a minimum of one PKHD1 mutation in more than 95% of families. Thus far, a total of 263 different PKHD1 mutations (639 mutated alleles) are included in the locus-specific database (www.humgen.rwth-aachen.de). Except for a few population-specific founder alleles and the common c.107C>T (p.Thr36Met) missense change, PKHD1 is characterized by significant allelic diversity, making mutation screening time-consuming and labor-intensive. Mutations are distributed throughout the gene's coding sequence; however, they are not equally scattered. Thus, we aimed to set up an algorithm for efficient molecular genetic diagnostics in ARPKD. A total of 80% of known PKHD1 mutations can be identified if a subset of 27 out of 77 DHPLC fragments is screened. The current study provides an essential platform for PKHD1 mutation screening in a routine setting that will largely alleviate molecular genetic diagnostics in patients suspected to have ARPKD.

• Authors: Carsten Bergmann, Fabian Küpper, Christian Dornia, Frank Schneider, Jan Senderek, Klaus Zerres
• Journal: Human mutation (Hum Mutat) Vol. 25 Issue 3 Pg. 225-31 (Mar 2005) ISSN: 1098-1004 [Electronic] United States
• PMID: 15706593 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Review)
• Copyright: (c) 2005 Wiley-Liss, Inc.

Chemical References

• PKHD1 protein, human
• Receptors, Cell Surface

Topics

• Algorithms
• Alleles
• Chromatography, High Pressure Liquid
• Cohort Studies
• DNA Mutational Analysis (methods)
• Databases, Factual
• Genes, Recessive
• Genetic Testing (methods)
• Haplotypes (genetics)
• Humans
• Open Reading Frames (genetics)
• Polycystic Kidney, Autosomal Recessive (genetics)
• Receptors, Cell Surface (genetics)
• Sensitivity and Specificity
• White People (genetics)