Mutations in the β-Tubulin Gene TUBB5 Cause Microcephaly with Structural Brain Abnormalities

Martin Breuss, Julian Ik-Tsen Heng, Karine Poirier, Guoling Tian, Xavier Hubert Jaglin, Zhengdong Qu, Andreas Braun, Thomas Gstrein, Linh Ngo, Matilda Haas, Nadia Bahi-Buisson, Marie-Laure Moutard, Sandrine Passemard, Alain Verloes, Pierre Gressens, Yunli Xie, Kathryn J.H. Robson, Deepa Selvi Rani, Kumarasamy Thangaraj, Tim Clausen, Jamel Chelly, Nicholas Justin Cowan, David Anthony Keays

The formation of the mammalian cortex requires the generation, migration, and differentiation of neurons. The vital role that the microtubule cytoskeleton plays in these cellular processes is reflected by the discovery that mutations in various tubulin isotypes cause different neurodevelopmental diseases, including lissencephaly (TUBA1A), polymicrogyria (TUBA1A, TUBB2B, TUBB3), and an ocular motility disorder (TUBB3). Here, we show that Tubb5 is expressed in neurogenic progenitors in the mouse and that its depletion in vivo perturbs the cell cycle of progenitors and alters the position of migrating neurons. We report the occurrence of three microcephalic patients with structural brain abnormalities harboring de novo mutations in TUBB5 (M299V, V353I, and E401K). These mutant proteins, which affect the chaperone-dependent assembly of tubulin heterodimers in different ways, disrupt neurogenic division and/or migration in vivo. Our results provide insight into the functional repertoire of the tubulin gene family, specifically implicating TUBB5 in embryonic neurogenesis and microcephaly.