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Projects
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.
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.
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.
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SCHOOL OF MEDICINE
