Tubulins, and microtubule
polymers into which they incorporate, play critical mechanical roles in neuronal function during cell proliferation, neuronal migration, and postmigrational development: the three major overlapping events of mammalian cerebral cortex development. A number of neuronally expressed
tubulin genes are associated with a spectrum of disorders affecting cerebral cortex formation. Such "tubulinopathies" include
lissencephaly/
pachygyria,
polymicrogyria-like malformations, and simplified gyral patterns, in addition to characteristic extracortical features, such as corpus callosal, basal ganglia, and cerebellar abnormalities.
Epilepsy is a common finding in these related disorders. Here we describe two unrelated individuals with infantile-onset
epilepsy and abnormalities of brain morphology, harboring de novo variants that affect adjacent
amino acids in a
beta-tubulin gene TUBB2A. Located in a highly conserved loop, we demonstrate impaired
tubulin and microtubule function resulting from each variant in vitro and by using in silico predictive modeling. We propose that the affected functional loop directly associates with the
alpha-tubulin-bound
guanosine triphosphate (
GTP) molecule, impairing the intradimer interface and correct formation of the alpha/
beta-tubulin heterodimer. This study associates mutations in TUBB2A with the spectrum of "tubulinopathy" phenotypes. As a consequence, genetic variations affecting all
beta-tubulin genes expressed at high levels in the brain (TUBB2B, TUBB3, TUBB, TUBB4A, and TUBB2A) have been linked with
malformations of cortical development.