Since no cytogenetic abnormalities have been found in association with ADPKD, flanking genetic markers have been required to define an interval--the PKD1 region--that contains the PKD1 gene.
The mean (SE) age of onset of ESRD is 56.3 (1.8) years for persons with the PKD1 form of ADPKD, and 68.7 (1.7) years for affected members of families in which ADPKD is not co-inherited with PKD1 markers (P = 0.01).
The most likely order of six of the probes from the telomere is palpha3'HVR.64 at the designated locus D16S85, CRI-0327 at D16S63, CRI-090 at D16S45, CRI-0129 at D16S56, CRI-0133 at D16S58, and CRI-0136 at D16S60, with the PKD1 locus for ADPKD between D16S85 and D16S63.
Sixty-eight individuals from six Italian families in which autosomal dominant polycystic kidney disease (ADPKD) is segregating, were typed in DNA polymorphisms linked to the PKD1 locus on chromosome 16.
The polymorphic DNA probe VK5B (D16S94) was mapped by genetic linkage in families from the Centre d'Etude de Polymorphisme Humain (CEPH) as being in the same interval as the autosomal dominant adult polycystic kidney disease locus (PKD1).
We studied 17 families with autosomal dominant polycystic kidney disease to compare presymptomatic diagnosis by ultrasonography with diagnosis by genetic-linkage studies and to relate clinical variation of the disease to whether the PKD1 mutation was implicated.
Linkage studies have been carried out using two probes (3'HVR and 24-1) linked to ADPKD on locus PKD1 and two probes (alpha 1-PstI and BamH-I/EcoRI-zeta 2 fragment) allowing detection of alpha-thalassemia with either a 3.7-kb deletion or a 4.2-kb deletion.
The localization of the autosomal dominant polycystic kidney disease locus (PKD1) within an array of anonymous polymorphic DNA sequences on chromosome 16 band p13 was determined by multipoint mapping.
Twenty families with autosomal dominant polycystic kidney disease from S. W. Thames Region were analysed using markers for chromosome 16p13.3, the site of the common mutation (PKD1).
A novel nonsense mutation in the PKD1 gene (C3817T) is associated with autosomal dominant polycystic kidney disease (ADPKD) in a large three-generation Italian family.
Using antibodies raised against the predicted gene product of PKD1, which is mutated in about 85% of ADPKD cases, we show that PKD1 is a 530-kD protein localized to the extracellular matrix of kidney, liver and cerebral blood vessels.
Analysis of the genomic sequence for the autosomal dominant polycystic kidney disease (PKD1) gene predicts the presence of a leucine-rich repeat. The American PKD1 Consortium (APKD1 Consortium).
Analysis of the deletions indicates that they inactivate PKD1, in contrast to the mutations reported in ADPKD patients, where in each case abnormal transcripts have been detected.
Although most mutations causing ADPKD in European populations have been mapped to the PKD1 locus on chromosome 16, some of them appear to be unlinked to this locus.
From these cases and a review of the literature, we draw the following conclusions: (1) so far, all fetal ADPKD kidneys that have been histologically studied have shown cystic dilatations; 28/32 of these fetuses had ultrasonographic manifestations of the disease and/or had sibs with an early-onset form of it; (2) these cysts can be found in newly formed nephrons (fetus 2), predominantly in the more mature nephrons of the deep cortex (fetus 1) or more sparsely distributed in the cortex (fetus 3); these different patterns may reflect different rates of progression of the disease; (3) in contrast to the histologic findings in adult kidneys, glomeruli seem to be predominantly affected in fetal ADPKD; (4) severe fetal expression of ADPKD seems to cluster in some families; and (5) so far, all DNA analyses performed in families with subjects presenting during the fetal or neonatal period have been consistent with linkage to the PKD1 locus.