ADPKD:Disease Spectrum &Genotype-Phenotype Correlations

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Molecular diagnosis of autosomal dominant
polycystic kidney disease (ADPKD) has proven difficult because of genetic and
allelic heterogeneity and the complex structure of the major gene, PKD1.
Consequently, the degree to which the marked phenotypic variability in the
severity of renal disease and expression of extrarenal manifestations
correlates with genotype is largely unknown. Using recent improvements to
specifically amplify the PKDI gene and temperature modulated heteroduplex
analysis (TMHA), we propose to develop rapid and accurate genetic
characterization of the ADPKD genes. Mutation detection rates of >80 percent
for PKD1 and >90 percent for PKD2 will be achieved during the project. The fate
and stability of mutant ADPKD proteins, polycystin-1 and -2, will be
investigated in patient-derived lymphoblastoid cell lines, epithelial cell
lines derived from a single cyst lining, and knockout mouse models of PkdI. The
mutational mechanism will be further explored by the isolation of individual
cyst lining, characterized by their immuno-reactivity to the polycystin
proteins, using laser capture microdissection. Genetic analysis of these cells
will reveal the importance of somatic events at the ADPKD genes and elsewhere
for cyst initiation and expansion. Phenotype/genotype correlations will be
explored in defined patient groups: renal insufficient; geographically defined
without referral or recognition bias; very early onset disease; late onset
disease; severe liver disease and vascular abnormalities. The ADPKD gene is
known to be a strong indicator of renal disease severity (PKD1 more severe than
PKD2) but the relative contribution of the two genes to extra-renal disease is
unknown. The prevalence of PKD2 in the general population is also largely
unknown. Correlations between the type and position of mutation in PKD1 and
PKD2 will be made to the severity of renal disease and to the different
phenotypic groups. These results will show if there are clear
phenotype/genotype correlations, that may have prognostic implications, reveal
more about the mutational mechanism and highlight important regions of the
polycystin proteins. Specific mutational mechanisms, such as an early embryonic
somatic mutation or the modifying effect of variants at the ADPKD allele
inherited from the normal parent, will be analyzed in early onset cases. This
study will help resolve questions about the mutational mechanism in ADPKD,
determine the role of somatic events, show the extent to which the ADPKD
genotype dictates clinical outcomes and generate phenotypically and
genotypically well characterized ADPKD populations that will be suitable for
testing the role of other genetic modifying factors.
Effective start/end date12/1/005/31/18


  • Medicine(all)