Human Molecular Genetics, Vol 6, 1473-1481, Copyright © 1997 by Oxford University Press
TJ Watnick, KB Piontek, TM Cordal, H Weber, MA Gandolph, F Qian, XM Lens, HP Neumann and GG Germino
The gene for the most common and severe form of autosomal dominant
polycystic kidney disease, PKD1, encodes a 14 kb mRNA that is predicted to
result in an integral membrane protein of 4302 amino acids. The major
challenge faced by researchers attempting to complete mutation analysis of
the PKD1 gene has been the presence of several homologous loci also located
on chromosome 16. Because the sequence of PKD1 and its homologs is nearly
identical in the 5' region of the gene, most traditional approaches to
mutation analysis cannot distinguish sequence variants occurring uniquely
in PKD1. Therefore, only a small number of mutations have been identified
to date and these have all been found in the 3', unique portion of the
gene. In order to begin analysis of the duplicated region of PKD1, we have
devised a novel strategy that depends on long-range PCR and a single
gene-specific primer from the unique region of the gene to amplify a
PKD1-specific template that spans exons 23-34. This 10 kb template,
amplified from genomic DNA, can be employed for mutation analysis using a
wide variety of sequence- based approaches. We have used our long-range PCR
strategy to begin screening for sequence variants with heteroduplex
analysis, and several affected individuals were discovered to have clusters
of base pair substitutions in exons 23 and 25. In two patients, these
changes, identified in exon 23, would be predicted to result in multiple
amino acid substitutions in a short stretch of the protein. This clustering
of base pair substitutions is unusual and suggests that mutation may result
from unique structural features of the PKD1 gene.
ARTICLES
An unusual pattern of mutation in the duplicated portion of PKD1 is revealed by use of a novel strategy for mutation detection
Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
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