Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype

doi:10.1016/S0140-6736(03)13773-7

The Lancet

Volume 361, Issue 9376, 28 June 2003, Pages 2196-2201

https://doi.org/10.1016/S0140-6736(03)13773-7 Get rights and content

Summary

Background

Patients with autosomal dominant polycystic kidney disease (ADPKD) are at risk of developing intracranial aneurysms, and subarachnoid haemorrhage is a major cause of death and disability. Familial clustering of intracranial aneurysms suggests that genetic factors are important in the aetiology. We tested whether the germline mutation predisposes to this vascular phenotype.

Methods

DNA samples from patients with ADPKD and vascular complications were screened for mutations throughout the PKD1 and PKD2 genes. Comparisons were made between the pkd1 and pkd2 populations and with a control PKD1 cohort (without the vascular phenotype).

Findings

Mutations were characterised in 58 ADPKD families with vascular complications; 51 were PKD1 (88%) and seven PKD2 (12%). The median position of the PKD1 mutation was significantly further 5′ in the vascular population than in the 87 control pedigrees (aminoacid position 2163 vs 2773, p=0·0034). Subsets of the vascular population with aneurysmal rupture, early rupture, or families with more than one vascular case had median mutation locations further 5′ (aminoacid position 1811, p=0·0018; 1671, p=0·0052; and 1587, p=0·0003).

Interpretation

Patients with PKD2, as well as those with PKD1, are at risk of intracranial aneurysm. The position of the mutation in PKD1 is predictive for development of intracranial aneurysms (5′ mutations are more commonly associated with vascular disease) and is therefore of prognostic importance. Since the PKD1 phenotype is associated with mutation position, the disease is not simply due to loss of all disease allele products.

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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Vascular Complications in Autosomal Dominant Polycystic Kidney Disease: Perspectives, Paradigms, and Current State of Play
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Autosomal dominant polycystic kidney disease (ADPKD) is the leading cause of inherited kidney disease with significant contributions to CKD and end-stage kidney disease. The underlying polycystin proteins (PC1 and PC2) have widespread tissue expression and complex functional roles making ADPKD a systemic disease. Vascular complications, particularly intracranial aneurysms (ICA) are the most feared due to their potential for devastating neurological complications and sudden death. Intracranial aneurysms occur in 8-12% of all patients with ADPKD, but the risk is intensified 4-5-fold in those with a positive family history. The basis for this genetic risk is not well understood and could conceivably be due to features of the germline mutation with a significant contribution of other genetic modifiers and/or environmental factors. Here we review what is known about the natural history and genetics of unruptured ICA in ADPKD including the prevalence and risk factors for aneurysm formation and subarachnoid hemorrhage. We discuss two alternative screening strategies and recommend a practical algorithm that targets those at highest risk for ICA with a positive family history for screening.
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Autosomal dominant polycystic kidney disease (ADPKD) in Tunisia: From molecular genetics to the development of prognostic tools
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A high prevalence of genetic kidney disease in Tunisia has been detected, and their study provides very important clinical and genetic information. Autosomal dominant polycystic kidney disease (ADPKD) is one of the main causes of morbidity and mortality associated with the kidneys in Tunisia. We present here clinical and genetic characteristics of a cohort of Tunisian patients with ADPKD. Nineteen Tunisian patients with ADPKD, among 4 familial cases and 11 sporadic cases, and 50 Healthy individuals were included in this cohort. Genetic studies of PKD1/2 were carried on using Sanger sequencing and MLPA. In our study, the mean age at diagnosis was 47 ± 18 years. In addition, 84.21% of cases present a family history of ADPKD. Overall, 57.89% of the affected individuals had HTA and 26.31% patients had hematuria. 15.78 % of the patient has extra-renal cysts i.e. one patient with splenic cysts and two patients had liver cysts. 57.89 % of patients were diagnosed with various extra-renal clinical presentations i.e. myopia, hernia, deafness, intracranial aneurysm, respiratory distress, hyperthyroidism, urinary tract infection and lower back pains. The PKD1 genotype showed earlier onset of ESRD compared to PKD2 genotype (43 vs. 55 years old). Six mutations have been detected in PKD1 gene. Among them, three were novels e.g. c.688 T>G, p.C230G and c.690C>G, p.C230W among exon 5 and c.8522A>G, p.N2841S among exon 23. In addition, thirteen single nucleotides polymorphisms have been reported in PKD1 gene. Among them, eleven previously reported in heterozygous state and two novel single nucleotides polymorphisms in heterozygous and homozygous state and predicted to be probable polymorphisms by computational tools: c.496C>T, p.L166= among the exon 4, and c.10165G>C and p.E3389Gln among the exon 31. Only three single nucleotides polymorphisms previously reported in ADPKD database have been identified in PKD2 gene. The description and analysis of our cohort can help in rapid and reliable diagnosis for early management of patients in Tunisia. Indeed, predictive genetic testing can facilitate donor evaluation and increase living related kidney transplantation.
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the prevalence of intracranial aneurysms and arachnoid cysts is higher in patients with autosomal dominant polycystic kidney disease (ADPKD) than in the general population. A genotype correlation was reported for intracranial aneurysms, but it is unclear for arachnoid cysts. Therefore, the genotype correlation with intracranial aneurysms and arachnoid cysts was investigated in ADPKD.
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PKD1-, PKD2- and no-mutation were identified in 137, 24 and 8 patients, respectively. Intracranial aneurysms and arachnoid cysts were found in 34 and 25 patients, respectively, with no significant difference in frequency. Genotype, sex, estimated glomerular filtration rate and age at ADPKD diagnosis significantly affected the age at brain MRI. The proportional hazard risk analyzed using the age at brain MRI adjusted by these four variables was 5.0-times higher in the PKD1 group than in the PKD2 group for arachnoid cysts (P = 0.0357), but it was not different for intracranial aneurysms (P = 0.1605). Arachnoid cysts were diagnosed earlier in the PKD1 group than in the PKD2 group (54.8 vs 67.7 years, P = 0.0231), but no difference was found for intracranial aneurysms (P = 0.4738) by Kaplan-Meier analysis.
this study demonstrated the correlation between arachnoid cysts and PKD1 mutation. The reported association of arachnoid cysts with advanced renal disease may be due to the common correlation of these factors with PKD1 mutation.

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Mechanisms of DiseaseAssociation of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Clinical evaluation of families

Results

Discussion

GLOSSARY

Am J Kidney Dis

Lancet

Am J Hum Genet

Am J Hum Genet

Kidney Int

Cell

Cell

Curr Biol

Intracranial aneurysms in autosomal dominant polycystic kidney disease

N Eng J Med

Intracranial arterial dolichoectasia in autosomal dominant polycystic kidney disease

J Am Soc Nephrol

Intracranial aneurysms in autosomal dominant polycystic kidney disease

Kidney Int

Spontaneous artery dissection: is it part of the spectrum of autosomal dominant polycystic kidney disease?

Nephrol Dial Transplant

Value of magnetic resonance angiography for detection of intracranial aneurysm in autosomal dominant polycystic kidney disease

J Am Soc Nephrol

Management of cerebral aneurysms in autosomal dominant polycystic kidney disease

J Am Soc Nephrol

Causes of death in autosomal dominant polycystic kidney disease

J Am Soc Nephrol

Mechanisms of Disease
Association of mutation position in polycystic kidney disease 1 (PKD1) gene and development of a vascular phenotype