Genome-wide association studies (GWAS) have identified up to 30 loci that associate
with increased risk of coronary artery disease or myocardial infarction. Here, I tested the
function of one locus that changed the amino acid sequence of a mitochondrial matrix
protease called paraplegin (SPG7) that performs critical quality assurance functions.
Loss-of-function mutations in this protease are associated with hereditary spastic
paraplegia. Here, I show that this variant that changes an arginine to a glutamine at
position 688 within the protease domain is a gain-of-function. Cells bearing this variant
have increased mitochondrial fusion and number, produce higher levels of reactive
oxygen species and have increased cellular proliferation. Importantly, when expressed in
yeast, the Q688 variant of SPG7 rescues the growth arrest caused by a protease-deficient
mutation in AFG3L2. My study identifies a novel functional variant of SPG7 and
highlights the need to go beyond the GWAS paradigm.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OOU-OLD./22665 |
| Date | 19 March 2012 |
| Creators | Almontashiri, Naif |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
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