TUBULINOPATHIES IN MALFORMATIONS OF THE CEREBRAL CORTEX

Abstract

<h3>Aims</h3> To further characterise the ‘tubulinopathy’ spectrum of overlapping brain malformations (including lissencephaly, polymicrogyria and mildly simplified gyral patterning) that arise from tubulin gene variations affecting neuronal proliferation, migration and post-migrational organisation during cerebral cortex development. <h3>Method</h3> A cohort of affected cases (n=13) with mild to unaffected cerebral cortex patterning, but with highly recognisable basal ganglia, corpus callosal and cerebellar malformations, were screened for gene-variations in a number of human brain-expressed tubulin genes. <h3>Results</h3> We describe two unrelated individuals with mildly simplified gyration and infantile-onset epilepsy, harbouring de novo variants that affect adjacent amino acids in a novel tubulinopathy gene, TUBB2A. We also report a further four mutations in TUBA1A, TUBB2B and TUBB3 (historically associated with lissencephaly, polymicrogyria and polymicrogyria/congenital fibrosis of the extraocular muscles respectively) in individuals with normal gyration but extra-cortical abnormalities characteristic of tubulin gene involvement. <h3>Conclusion</h3> We describe a highly stereotyped brain phenotype caused by mutations in four different genes (TUBA1A, TUBB2B, TUBB3 and a novel gene, TUBB2A), sharing high sequence homologies but with distinct spatial-temporal expression patterns. All beta-tubulins highly expressed during cerebral cortex development are now associated with brain malformations.