TY  - GEN
T1  - A C. elegans model for the rare human channelopathy, Timothy syndrome type 1
AU  - Lagoy, Ross
AU  - Kim, Heesun
AU  - Mello, Craig C
AU  - Albrecht, Dirk R
DO  - 10.17912/micropub.biology.000081
UR  - http://beta.micropublication.org/journals/biology/micropub-biology-000081/
AB  - Timothy syndrome (TS) type 1 is a rare genetic human disease caused by a gain-of-function (GOF) missense mutation G406R in the L-type voltage-gated calcium channel (VGCC) a1 subunit gene CACNA1C, which results in severe cardiac arrhythmia and autism (Splawski et al. 2004). The C. elegans ortholog is EGL-19 (Fig. 1a), which is expressed in muscle and neurons (Lee et al. 1997). GOF mutations in egl-19 cause myotonic phenotypes, while reduction-of-function (ROF) mutants are flaccid, variably elongated, and egg-laying defective, and lethal mutations cause paralysis with arrested elongation at the two-fold stage (Pat) (Lee et al. 1997). Additionally, treatment of embryos with nemadipine-A, an antagonist of L-type VGCCs, causes a severe variable abnormal (Vab) phenotype like some ROF hatchlings (Kwok et al. 2006). Neural and muscle cells derived from patients with TS type 1 also yield impaired channel inactivation (Yazawa et al. 2011; Paşca et al. 2011). Therefore, we hypothesized that insertion of the human TS type 1 GOF mutation in the C. elegans genome (G369R) by CRISPR-Cas9 homologous recombination (HR) would cause observable changes in calcium dynamics and serve as a new animal disease model of TS to broadly investigate molecular mechanisms in vivo.
PY  - 2018
JO  - microPublication Biology
ER  -