Date of Award
Doctor of Philosophy (PhD)
ATP-sensitive potassium (KATP) channels are composed of inward-rectifying potassium channel pore-forming subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor subunits (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively). These channels couple metabolism to excitability in multiple tissues. Mutations in ABCC9 have been linked to Cantú syndrome (CS), a multi-organ disease characterized by congenital hypertrichosis, distinct facial features, osteochondrodysplasia, and cardiac defects. Additionally, two ABCC9 mutation-negative patients, exhibiting clinical hallmarks of CS, have been identified as having KCNJ8 mutations. This body of work is focused on determining the functional consequences and molecular mechanisms of documented CS-associated ABCC9 and identified KCNJ8 mutations. These mutations were engineered into recombinant cDNA clones and expressed as functional channels. Macroscopic rubidium (86Rb+) efflux assay experiments demonstrate that KATP channels formed with SUR2 and Kir6.1 mutant subunits both result in gain of function in KATP activity. Inside-out patch-clamp electrophysiological experiments show that there are at least 3 mechanisms by which these mutations alter KATP channel activity, including: 1) an SUR2 mutation that indirectly decreases ATP sensitivity by allosteric changes, 2) a Kir6.1 mutation that increases channel-open probability, and thereby indirectly decreases ATP sensitivity, and 3) mutations in SUR2 that increase channel activation in response to MgADP. Taken together, CS-associated ABCC9 or KCNJ8 mutations result in enhanced KATP activity that underlies the cardinal features of Cantu Syndrome.
Chair and Committee
Colin G Nichols
Sarah England, Chris Lingle, Jeanne Nerbonne, Maria Remedi
Cooper, Paige, "Functional Consequences of Cantu Syndrome Associated Mutations in the ATP Sensitive Potassium Channel" (2015). Arts & Sciences Electronic Theses and Dissertations. 644.