Wanhao Chi

Graduate Student, Xiaoxi Zhuang Lab

BSD 2018 Donald Steiner Award recepient

“It is well known that complete loss of essential genes results in embryonic lethality or sterility. However, it is less studied how mild deficiency in essential genes may confer susceptibility to diseases depending on gene-gene or gene-environment interactions. My thesis work on Drosophila models demonstrates a concrete example of interactions between dietary micronutrients and mild deficiency in the essential gene PNPO that contribute to diseases. PNPO converts inactive forms of Vitamin B6 (VB6) in the diet to the only active form PLP, which is a co-factor for more than 140 enzymes including enzymes for the synthesis of neurotransmitters dopamine, serotonin, and GABA. In humans, severe PNPO deficiency leads to neonatal epileptic encephalopathy. I have identified a partial loss of function mutation in Drosophila PNPO that causes seizures only under dietary VB6 restriction conditions. To systematically study the interactions between various PNPO deficiencies and environmental conditions, I have generated knock-in lines with different degrees of severity in PNPO deficiency using CRISPR/Cas9. These knock-in lines show different degrees of severity in seizures and lifespan depending on mutation x dietary VB6 interactions. For the rest of my thesis, I am focusing on the in vivo functional impact of PNPO in different cell types as well as the impact of different PNPO mutations on PNPO protein trafficking and function. I am also collaborating with neurologists to study the genetics of PNPO on adult epilepsy patients. ”---Wanhao Chi