Mechanisms of DiseaseAssociation of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype
Introduction
Autosomal dominant polycystic kidney disease (ADPKD) is a common, systemic, monogenic disorder characterised by progressive development of renal cysts and specific extrarenal abnormalities. The extrarenal disease most commonly associated with premature death and disability is a vascular phenotype consisting of ruptured intracranial aneurysms, resulting in subarachnoid haemorrhage, and more rarely, intracranial dolichoectasia, dilatation of the aortic root, and dissections of the thoracic aorta and cervicocephalic arteries.1, 2, 3, 4 The prevalence of asymptomatic intracranial aneurysms in ADPKD has been estimated at about 8%, roughly five times higher than that found in the general population.1, 5, 6 Death due to subarachnoid haemorrhage occurs in about 6% of patients with ADPKD,7 with aneurysmal rupture on average at age 41 years, a decade earlier than sporadic cases, but similar to the average age for familial intracranial aneurysms.3, 6, 8 Genetic factors probably influence the occurrence of the vascular phenotype in ADPKD. Striking familial clustering of intracranial aneurysms has been observed, with the rate of aneurysms detected five times higher in patients with a family history of ruptured intracranial aneurysms than in those without a family history.5 In a recent study, 15 (7·5%) of 199 ADPKD families accounted for all definite ruptured intracranial aneurysms in a population of ADPKD patients, with more than one vascular case in five families.9 Furthermore, ADPKD accounts for 9% of familial intracranial aneurysms.10
ADPKD is genetically heterogeneous. Two genes, pkd1 (about 85% of cases) and PKD2 (15% of cases), have been identified and characterised. They encode related proteins, polycystins 1 and 2.11, 12 Polycystin 2 is an ion channel with a possible role in regulation of intracellular calcium ion concentrations, and polycystin 1 may be involved in cell-cell interactions.13 Both proteins are expressed in vascular smooth muscle and endothelia, which suggests a direct role in the vascular manifestations of ADPKD.14, 15, 16 Furthermore, knockout models of murine Pkd1 and Pkd2 develop a phenotype of vascular leakage and blood-vessel rupture in homozygous fetuses from embryonic day 12·5, indicating a role for the polycystins in vascular integrity.16, 17
Intracranial aneurysms have been described in both pkd1 and pkd2 families,3, 18 but the respective rates of vascular complications are unknown. The description of a specific mutation in exon 15 of PKD1 in two patients with intracranial aneurysms reinforced the view from familial clustering that the germline PKD1 mutation may be important in predisposing to the vascular phenotype.19 Recently, with improved mutation analysis, the first clear phenotype-genotype correlations have been described in PKD1. The location of the mutation was associated with the severity of renal disease; 5′ mutations to PKD1 are associated with earlier end-stage renal disease.20
In this study, we investigated whether the type or the position of germline mutations in PKD1 or PKD2 are associated with the development of vascular complications.
Section snippets
Clinical evaluation of families
Approval from the institutional review board or ethics committee was obtained at all centres in this study, and all participants gave informed consent. Enrolment of an ADPKD family in the study required demonstration of the disease by conventional imaging criteria and documented evidence of an intracranial aneurysm or other vascular anomaly as mentioned above. A family history was taken from the proband, or a living relative, and a pedigree prepared to document each patient with a suspected
Results
Mutations were sought in ADPKD families with vascular disease to assess the relative prevalence of pkd1 and pkd2 and to see whether specific mutations were associated with intracranial aneurysms. 83 pedigrees were screened for mutations throughout the entire PKD1 and PKD2 genes; mutations were detected in 58 families (70%). Mutations were characterised as previously outlined.22 The occurrence of an intracranial aneurysm was defined rigorously, and only families in which there was a clearly
Discussion
We have defined a large ADPKD population characterised by the occurrence of disease-associated vascular complications. Mutation analysis of this population allowed us to identify pkd1 and pkd2 pedigrees and led to the discovery that mutation position in PKD1 is a strong predictor for the development of vascular complications. An important conclusion is that PKD2 patients are at risk of vascular complications of ADPKD; intracranial aneurysms were identified in seven PKD2 families, including one
GLOSSARY
- denaturing high-performance liquid chromatography
- An automated method to identify mutations in DNA sequences that manifest as a heteroduplexes.
- dominant negative mutation
- Generates an abnormal protein that antagonises the mutagenic effect by binding the wildtype protein or an interacting ligand in a nonfunctional complex.
- heteroduplex
- Double-stranded DNA fragment that has a mismatch between the two strands due to a mutation. The mismatched bases cannot pair as normal and so destabilise the DNA
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