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Title: Frameshift mutation-induced alternative translation initiation as a mechanism for migraine induction involving two-pore-domain potassium channels

Guillaume Sandoz

Université Cote d’Azur, France

Biography

Dr. Edward studied Chemistry at the Sofia University, Bulgaria and graduated as MS in 1999. She then Guillaume Sandoz is head of the Biology of Ion Channels (BIC) at the institute of Biology Valrose (UMR7277 & Inserm-U1091). He is a molecular and cellular neuroscientist with a strong background in ion channel structure and function. After a PhD on the regulation of the pre-synaptic voltage-dependent calcium channels, he joined the Lazdunski and Lesage Labs as a post-doc then as a “chargé de recherche” at the Institut of Cellular and Molecular Pharmacology in Nice (2004-2009), France, where he worked on the proteomic of K2P channels with the support of CNRS.  In 2009, Guillaume went at the Isacoff lab, UC Berkeley. At Berkeley, Guillaume worked on several aspect of the K2P pharmacology then he determined the molecular mechanisms underlying the fluoxetine effect on K2P channels.  In 2012, he started a new team called “Biology of Ion Channels” at the Institut of Biology Valrose (iBV) in Nice, France. The team is working on the physiology and pathological implication of K2P channels by using new optogenetic and single molecule techniques.

Abstract

It is often unclear why some genetic mutations to a given gene contribute to neurological disorders while others don't. For instance, two mutations have previously been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2 bp frameshift mutation, and TRESK-C110R. Both mutants inhibit TRESK, but only TRESK-MT increases sensory neuron excitability and is linked to migraine. Here we identify a new mechanism termed frameshift mutation-induced Alternative Translation Initiation (fsATI), that may explain why only TRESK-MT is associated with migraine. fsATI leads to the production of a second protein fragment, TRESK-MT2, which co-assembles with and inhibits TREK1 and TREK2, two other two-pore-domain K+ channels, to increase trigeminal sensory neuron excitability leading to a migraine-like phenotype in rodents. These findings identify TREK1 and 2 as potential molecular targets in migraine and suggest that fsATI should be considered as a distinct class of mutations.
Audience take away:
• We demonstrate that migraine-associated frameshift mutations of TRESK, a two-pore-domain K+ channel, lead to the production of a second protein fragment, which carries the pathophysiological function by inhibiting TREK1 and 2, due to a mechanism called frameshift mutation-induced Alternative Translation Initiation (fsATI)
• This mechanism for transmission of inherited diseases is knew and need to be consider when analyzing gene mutations