PT  - JOURNAL ARTICLE
AU  - Driver, Ashley M.
AU  - Pitstick, Amy L.
AU  - Mayhew, Chris N.
AU  - Kline-Fath, Beth
AU  - Saal, Howard M.
AU  - Stottmann, Rolf W.
TI  - A <em>de novo</em> missense mutation in <em>TUBA1A</em> results in reduced neural progenitor survival and differentiation
AID  - 10.1101/201814
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 201814
4099  - http://biorxiv.org/content/early/2017/10/16/201814.short
4100  - http://biorxiv.org/content/early/2017/10/16/201814.full
AB  - 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.