There are a large number of autosomal dominant (AD) genetic diseases in man that result from inactivating mutations in the affected gene. However, in many of these diseases, the basis of disease expression and the dominant pattern of inheritance are unclear. Capillary malformation-arteriovenous malformation (CM-AVM) is an AD vascular disease that is caused by inactivating mutations of the RASA1 gene. We have recently discovered that in normal human blood vascular endothelial cells (BEC) the RASA1 gene is subject to a type of gene inactivation known as random monoallelic expression (RME). Thus, in a substantial fraction of BEC, only one of two RASA1 alleles is expressed in any one cell. Therefore, we predict that in CM-AVM patients, RME at the RASA1 locus, combined with germline RASA1 mutation, results in total loss of functional RASA1 protein in BEC, which may explain lesion development and the dominant pattern of inheritance. Furthermore, up to eight percent of human autosomal genes are thought to be subject to RME, which raises the possibility that RME may be an important hitherto overlooked mechanism in the pathogenesis of a number of AD diseases in man. A long-term goal of the King laboratory is to understand mechanisms of intracellular signal transduction in mammalian cells and their role in health and disease. The overall objective of this application, which is consistent with this long-term goal, i to understand the potential contribution of RME to the development of human AD disease. Our central hypothesis is that RME is an essential component of a number of different AD diseases in man. The rationale for these studies is that they will result in a more complete understanding of the genetic mechanisms involved in the pathogenesis these diseases. We propose to objectively test our central hypothesis and, thereby, attain the objective of this application through the pursuit of two specific aims. In the first specific aim, we will determine if RME drive the development of blood vascular lesions in CM-AVM. This will be assessed through genetic analysis of BEC derived directly from blood vascular lesions of CM-AVM patients. In the second specific aim, we will examine the possibility that RME is necessary for the development of a number of other AD diseases in man, first through analysis of gene expression patterns in relevant normal cell types. The proposed studies are innovative because they would represent the first demonstration of a role for RME in a human disease and will address the possibility as to whether this is a general mechanism in AD disease etiology. The pro- posed studies are significant because of their potential to lead to new types of therapy for these diseases.

Public Health Relevance

The proposed studies are relevant to public health because they are expected to reveal a role for a gene inactivation mechanism in the pathogenesis of a number of inherited diseases in man. Knowledge gained may lead to the design of new drugs to treat these diseases and this, in turn, is expected to reduce discomfort and morbidity associated with these diseases. Thus, proposed studies are relevant to the part of the NIH mission that aims to extend healthy life and reduce the burdens of illness and disability.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Exploratory/Developmental Grants (R21)
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Genetics of Health and Disease Study Section (GHD)
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Coulombe, James N
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
United States
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Lapinski, Philip E; Doosti, Abbas; Salato, Valerie et al. (2018) Somatic second hit mutation of RASA1 in vascular endothelial cells in capillary malformation-arteriovenous malformation. Eur J Med Genet 61:11-16