Genetic Analysis of Complex Malformations of Cortical Development
Principle Investigator: Rolf Stottmann, PhD
The developing brain highly expresses multiple tubulin genes. Variants in these tubulin genes cause many severe malformations in human forebrain development, called the “tubulinopathies.” The human genetics studies now show there is a spectrum of disease arising from tubulin mutations, but the vast majority of those identified to date are de novo, heterozygous missense mutations. This suggests that a tubulin monomer protein is being produced, but acting in an inappropriate manner within the cell. Complementary loss of function studies have not been done on any of the implicated genes. A deeper understanding of the etiology of the human malformations and requirements for individual tubulin genes is essential to understanding how to treat patients with tubulin mutations.
Our research aims to understand why and how tubulin mutations cause malformations of cortical development. Our central hypothesis is that the human tubulin missense, de novo variants cause cortical malformations through dominant-negative effects on microtubule function and/or tubulin monomer protein-protein interactions. By answering some of these basic questions about tubulin biology, we are poised to contemplate the best therapeutic intervention(s). Recent studies have demonstrated that treatments of cortical malformation syndromes in an already malformed brain can ameliorate some symptoms. Thus, a greater understanding of the tubulinopathy developmental disorders could open some promising doors to fruitful treatments.