Acquired uniparental isodisomy and other somatic "second-hits" explain why glomuvenous malformations are multifocal
(2010)
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- Authors
- Supervisors
- Vikkula, Miikka
- Abstract
- (en) The goal of this thesis project was to unravel pathophysiological mechanisms playing a role in the development of glomuvenous malformations (GVMs). This work focused particularly on mechanisms involved in their multifocal and localized nature, and the involvement of somatic 'second-hit' mutations occurring in the glomulin gene. RNA in situ hybridization, performed in our laboratory, allowed us to determine the beginning of glomulin expression during embryonic development. Glomulin was first detected at embryonic day E10.5 in the cardiac outflow tract. Later, its expression was restricted to vascular smooth muscle cells, with a limited expression in the perichondrium (McIntyre et al, 2004). This likely suggested that the dysfunction, causing GVMs, resides in vascular smooth muscle cells. However, tissue heterogeneity had to be considered. One somatic 'second-hit' mutation had been identified in a resected GVM by our group (Brouillard et al, 2002), allowing us to hypothesize that GVMs are caused by the association of an inherited and a somatic 'second-hit' mutations. This could also explain the phenotypic variability observed within patients of a same family, existence of healthy carriers and apparition of new lesions in time. We collected 19 resected GVMs and identified somatic 'second-hit' mutations in 12 of them, the majority being somatic acquired uniparental isodisomies of the whole chromosome 1 short arm. Another part of this thesis project aimed to identify glomulin-interacting partners and putative signaling pathway(s) in which glomulin could be involved (Annex 1). By using yeast two-hybrid experiments and glomulin as a bait two aliquots of human cardiac cDNA library were screened. However, we did not find validated glomulin-interacting partners.
- Affiliations
Citations
Aerts, V. (2010). Acquired uniparental isodisomy and other somatic “second-hits” explain why glomuvenous malformations are multifocal. https://hdl.handle.net/2078.5/149151