Projects
Elastin Gene Mutations in Vascular and Skin Diseases
The objective of this project is to understand the mechanisms by which elastin gene mutations can lead to either of two distinct inherited diseases, supravalvular aortic stenosis (SVAS), or cutis laxa. We have shown that SVAS is caused by heterozygous loss of function mutations, leading to decreased elastin deposition and increased vascular cell proliferation. In contrast, our results indicate that autosomal dominant cutis laxa mutations result in the synthesis and incorporation of mutant elastin into the extracellular matrix, leading to structural abnormalities within elastic fibers. To investigate the disease mechanisms associated with cutis laxa further, we generated a mouse model by transgenic expression of a human elastin mutation. The animals showed lung airspace enlargement and increased compliance of the skin partially recapitulating the human disease. We will use this animal model to investigate potential therapeutic interventions that may be beneficial for patients with cutis laxa and pulmonary emphysema.
Gene Discovery in Cutis Laxa
Cutis laxa characterized by extensive genetic heterogeneity and known genes, such as the elastin gene, explain only about 20% of the cases. Therefore the goal of this project is to identify the genetic bases of new cutis laxa syndromes. We have started with the evaluation of candidate genes. These studies led to the identification of a fibulin-4 gene mutation as a cause of a new recessive cutis laxa syndrome associated with bone fragility, vascular tortuosity and developmental emphysema. In addition to candidate gene studies we have initiated a genetic mapping and positional cloning approach as an unbiased way of identifying novel cutis laxa genes.
Elastic Fiber Genes and Susceptibility to Common Diseases
Our studies on cutis laxa show that elastin gene mutations can cause aortic aneurysms and pulmonary emphysema. Both aneurismal diseases and pulmonary emphysema are common and have significant heritable risk. Could alleles in elastin and related genes contribute to the risk of these common diseases? Our initial studies showed genetic association of ruptured intracranial aneurysms with single nucleotide polymorphisms in the elastin gene. We now investigate the impact of these alleles on elastin gene expression and alternative spicing.