Genetic Mechanisms of Neurofibromatosis-Related Arteriopathy and Renovascular Hypertension
Abstract
Background: Renovascular hypertension (HTN) resulting from renal artery and abdominal aortic narrowing is due to a process known as arterial dysplasia (AD) and is an important cause of high blood pressure in children that may lead to heart failure, stroke, and early death. Neurofibromatosis type 1 (NF-1) is a common cause of pediatric renovascular HTN. A third of pediatric AD patients in the University of Michigan experience carry a diagnosis of NF-1, and others have described vascular involvement in nearly 20% of individuals with NF-1. It remains unclear why some children with NF-1 develop AD. The relationship of specific gene mutation in the NF1 gene to the severity of disease has not been previously reported. The possibility of mutations in tissues that were not present in the original fertilized egg (“somatic mutations”) has not been previously explored as a cause or pediatric AD. NF-1 is characterized by variable symptoms and disease presentation. The protein product of the neurofibromin gene (NF1) is involved in regulating the growth of several cell types, including those that make up the arterial wall, in particular, vascular smooth muscle cells (VSMCs). Neurofibromin regulates a cell-signaling pathway (Ras-Erk), and it is speculated that vascular cells that have lost neurofibromin will develop excessive tissue on the inside of the artery resulting in narrowing. If these same vascular cells are removed from mouse models of NF-1, the cells grow more rapidly in culture than expected. Research Questions and/or Concepts: The overall goal of our proposed study is to identify the underlying causes of arterial disease in NF-1. We are conducting unbiased genetic analyses of pediatric patients with AD by examining the subset of DNA (genetic “code”) that encodes proteins (exons) across the entire human genome. Thus far, our preliminary data have confirmed damaging NF1 mutations in approximately 25% of cases pediatric renovascular hypertension cases. Our overall goal is to identify why only a subset of patients with NF-1 develop AD. We hypothesize that specific mutations in the fertilized egg (“germline mutations”, such as those that can be inherited) and/or mutations in tissues after the egg is fertilized (“somatic mutations”) may underlie developmental AD. The information we gain in the proposed studies will improve our understanding of how genetic changes influence vascular disease in NF-1 patients and may identify novel targets for treatment of AD. Specific Aims: Aim 1. Characterize spectrum of mutations in the NF1 gene and other genes that may contribute to arterial disease in NF-1 using a whole exome sequencing approach integrated with RNASeq to identify mutations that alter proper RNA expression. Aim 2. Sequence DNA from arterial tissue to determine whether mutations have occurred in the tissue itself, which could contribute to abnormal growth of the artery or AD. We will look in patients with known NF-1 to see whether there is additional loss of genes in the arterial tissue and cells, and we will look in patients without a diagnosis of NF-1, but who may have a loss of NF-1 expression or function due to somatic mutation arising in the arterial tissue itself. Study Design: Blood and renal/aortic tissue from children with developmental AD and controls will continue to be recruited through an approved study, of which Dr. Ganesh is the Principal Investigator and Dr. Coleman (Vascular Surgery) is Co-Investigator. To expand on our previous genetic analysis presented in preliminary data, we will sequence a larger group of patients and use sophisticated DNA and RNA sequence analysis methods to identify genetic variants that may be related to NF-1 arterial disease. We will use new technology (“MIPS,” molecular inversion probe sequencing) to deeply sequence the NF1 gene and/or exome sequencing of arterial tissue and cells to determine whether somatic mutation is a relevant mechanism for pediatric
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010213
Entities
People
- Santhi Ganesh
Organizations
- United States Army
- University of Michigan