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A de novo missense mutation in TUBA1A results in reduced neural progenitor survival and differentiation

Mutations in tubulins have been implicated in numerous human neurobiological disorders collectively known as “tubulinopathies.” We identified a patient with severe cortical dysgenesis and a novel de novo heterozygous missense mutation in Tubulin Alpha 1a (TUBA1A, c.1225 G>T). Induced pluripotent stem cells derived from this individual were differentiated into two dimensional neural rosette clusters to identify underlying mechanisms for the severe cortical dysgenesis phenotype. Patient-derived clones showed evidence of impaired neural progenitor survival and differentiation with abnormal neural rosette formation, increases in cell death, and fewer post-mitotic neurons. These features correlate with the drastically underdeveloped cortical tissues seen in the proband. This is the first experimental evidence in human tissue suggesting a mechanism underlying the role for TUBA1A in cortical development. SUMMARY STATEMENT Variants in tubulin genes often lead to severe congenital brain malformations. Here we identify a new mutation in TUBA1A and use iPSCS to show this alters proliferation, differentiation and survival of neural progenitors.