Dataset Information

A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.

ABSTRACT: Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci (PKD1, PKD2, and PKD3) that account for the disease. Mutations in the PKD2 gene, on the long arm of chromosome 4, are expected to be responsible for approximately 15% of cases of ADPKD. Although ADPKD is a systemic disease, it shows a focal expression, because <1% of nephrons become cystic. A feasible explanation for the focal nature of events in PKD1, proposed on the basis of the two-hit theory, suggests that cystogenesis results from the inactivation of the normal copy of the PKD1 gene by a second somatic mutation. The aim of this study is to demonstrate that somatic mutations are present in renal cysts from a PKD2 kidney. We have studied 30 renal cysts from a patient with PKD2 in which the germline mutation was shown to be a deletion that encompassed most of the disease gene. Loss-of-heterozygosity (LOH) studies showed loss of the wild-type allele in 10% of cysts. Screening of six exons of the gene by SSCP detected eight different somatic mutations, all of them expected to produce truncated proteins. Overall, >/=37% of the cysts studied presented somatic mutations. No LOH for the PKD1 gene or locus D3S1478 were observed in those cysts, which demonstrates that somatic alterations are specific. We have identified second-hit mutations in human PKD2 cysts, which suggests that this mechanism could be a crucial event in the development of cystogenesis in human ADPKD-type 2.

SUBMITTER: Torra R

PROVIDER: S-EPMC1377933 | biostudies-other | 1999 Aug

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.

Torra R R Badenas C C San Millán J L JL Pérez-Oller L L Estivill X X Darnell A A

American journal of human genetics 19990801 2

Autosomal dominant polycystic kidney disease (ADPKD) is genetically heterogeneous, with at least three chromosomal loci (PKD1, PKD2, and PKD3) that account for the disease. Mutations in the PKD2 gene, on the long arm of chromosome 4, are expected to be responsible for approximately 15% of cases of ADPKD. Although ADPKD is a systemic disease, it shows a focal expression, because <1% of nephrons become cystic. A feasible explanation for the focal nature of events in PKD1, proposed on the basis of ...[more]

PMID: 10417277

Similar Datasets

Project description:Background and objectivesIt is assumed that in autosomal dominant polycystic kidney disease (ADPKD), kidney function remains in the normal range for several decades because of hyperfiltration of remnant nephrons. In this study, we investigate the extent to which patients with ADPKD hyperfilter.Design, setting, participants, & measurementsIn this cross-sectional study, we measured GFR as urinary clearance using continuous infusion of 125I-iothalamate. Kidney function reserve capacity was determined as increase in measured GFR after adding a dopamine infusion of 4.4-6 mg/h. Potential kidney donors were used as healthy controls and matched by age and sex to patients with ADPKD for comparisons across age groups and CKD stages. Hyperfiltration was defined by a loss of kidney function reserve capacity compared with healthy controls.ResultsA total of 300 participants were studied. In the youngest age group (18-29 years), measured GFR was not different between patients with ADPKD and healthy controls (103±21 versus 111±9 ml/min per 1.73 m2; P=0.14). In this age group kidney function reserve capacity was higher compared with healthy controls (11.1%±8.3% versus 5.3%±6.5%; P=0.04). Moreover, kidney function reserve capacity was similar to healthy controls in patients with ADPKD with early-stage disease (eGFR?60 ml/min per 1.73 m2), either overall or when divided into fast or slow progressors according to their Mayo height-adjusted total kidney volume class. However, in patients with ADPKD, lower measured GFR was associated with lower kidney function reserve capacity (?=1.0 [95% confidence interval, 0.5 to 1.5] % per 10 ml/min per 1.73 m2; P<0.001). Kidney function reserve capacity was therefore lower compared with healthy controls at older age and later CKD stages.ConclusionsPatients with early-stage ADPKD, either classified as having rapidly or slowly progressive disease, are able to increase their GFR in response to dopamine. Hyperfiltration, defined by a loss of kidney function reserve capacity, may therefore not be an early phenomenon in ADPKD.

Dataset Information

A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.

Publications

A loss-of-function model for cystogenesis in human autosomal dominant polycystic kidney disease type 2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets