Determinants of Aneurysm Formation in Autosomal Dominant Polycystic Kidney Disease
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is the most common form of inherited kidney disease worldwide that is also associated with a 5- to 10-fold risk of brain aneurysms or dilations of blood vessel in the brain. ADPKD has also been linked with aneurysms in other large blood vessels in the body such as the aorta. This is an important problem because brain aneurysms in particular often rupture before kidney failure occurs, which can result in significant disability and/or death. Aneurysms in ADPKD cluster in certain ADPKD families, which suggests that a genetic predisposition plays an important role. Although a high percentage of ADPKD families (~25%) report a history of brain aneurysms, there have been no comprehensive studies of this problem. In this proposal, we will combine the efforts of two expert groups to tackle this issue for the first time. Several research groups including ours have conducted mutation screening in individuals with ADPKD and vascular complications to test whether there are specific mutations in either of the two main ADPKD genes (PKD1 or PKD2) that are more likely to result in aneurysms. These studies have identified a mutation in the PKD1 gene that occurs in ~6% of individuals with ADPKD and aneurysms. This mutation is predicted to yield a shortened PKD1 protein that we speculate is secreted outside of the cell and could affect the tissues or matrix that hold cells together. This is an attractive hypothesis because defects in other matrix proteins have been shown to cause aneurysms. In the Aim 1, we will model this aneurysm-associated human PKD1 mutation in mice and then study its effects in blood vessels. We will determine whether these mice develop aneurysms, whether the PKD1 protein is secreted into the matrix surrounding blood vessels and if this results in alterations in signaling pathways that have been associated with vascular aneurysms. Since not all members of ADPKD families with aneurysms develop this complication, we also hypothesize that there are other genes that affect the risk for aneurysm formation in the setting of a PKD gene mutation. Our preliminary data in mouse models show that a combination of a PKD1 gene mutation with a mutation in another aneurysm-related gene results in an enhanced deterioration in the structure of blood vessel walls. To study the possibility of gene-gene interactions in humans, we have already collected DNA from ~150 individuals with ADPKD and aneurysms, and in Aim 2 we plan to expand this cohort to ~600 individuals. We will survey DNA changes using two different strategies (whole exome sequencing and genome-wide association study) with a goal of identifying alterations in other genes or families of genes that might predispose ADPKD patients to blood vessel aneurysms. These studies will allow us to identify additional genetic risk factors and may also provide clues about what causes aneurysms in ADPKD patients. This proposal is significant because it will address the biology of a devastating complication of ADPKD that has been largely neglected. Although new therapies are being developed to treat kidney disease in ADPKD, if a patient dies of a ruptured aneurysm, these treatments will be in vain. We anticipate that an improved understanding of the genetic basis of aneurysms in ADPKD will allow us to develop improved strategies for earlier detection, prevention, and treatment of this potentially catastrophic ADPKD complication.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010763
Entities
People
- Stefan Somlo
Organizations
- United States Army
- Yale University