Project Details
Projekt
Molecular characterization of TUBB4 mutations
Subject Area
Molecular and Cellular Neurology and Neuropathology
Molecular Biology and Physiology of Neurons and Glial Cells
Molecular Biology and Physiology of Neurons and Glial Cells
Term
from 2014 to 2020
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 262431880
We recently identified mutations in the beta Tubulin 4 (TUBB4 or TUBB4A) gene as the cause of DYT4 dystonia. DYT4 is characterized by prominent whispering dysphonia and generalized dystonia. With the detection of mutations in a tubulin gene in dystonia, a novel pathway, i. e. disruption of the cytoskeleton, has been implicated in the pathophysiology of dystonia warranting functional characterization. In the present proposal, we aim to elucidate the spectrum and functional consequences of TUBB4 mutations with the following three specific aims: (1) To determine the spectrum of dystonic phenotypes caused by mutations in TUBB4, we will sequence all coding exons in ~2000 patients with different forms of dystonia/dystonic syndromes. (2) To identify the impact of known and novel mutations in TUBB4 on the molecular level, we will analyze mRNA levels, protein stability, and subcellular localization of the three known and up to two newly identified mutants and wildtype TUBB4. For this, we will primarily use a biologically relevant cell model. i.e. induced pluripotent stem cell (iPSC)-derived neurons generated from our mutation carriers, as well as TALEN-corrected isogenic control lines. (3) To study neuronal morphology and axonal transport in iPSC-derived neurons, we will analyze mitochondrial transport and neurite outgrowth and test the ability of a tubulin-stabilizing agent to rescue TUBB4-related neuronal dysfunction.
DFG Programme
Research Grants
