Mutations in the beta-tubulin gene TUBB2B result in asymmetrical polymicrogyria

Polymicrogyria is a relatively common but poorly understood defect of cortical development characterized by numerous small gyri and a thick disorganized cortical plate lacking normal lamination. We show an association between bilateral asymmetrical polymicrogyria and mutations in a -tubulin gene, , in four patients and a 27 GW (gestational week) fetus. de novo β TUBB2B Neuropathological examination of the fetus revealed an absence of cortical lamination associated with the presence of ectopic neuronal cells in the white matter, and in the leptomeningeal spaces due to breaches in the pial basement membrane. In utero RNAi-based inactivation demonstrates that is required for neuronal migration. We also show that two disease-associated TUBB2B mutations lead to an impaired formation of tubulin heterodimers. These observations, together with previous data, demonstrate that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly/pachygyria, but also polymicrogyria malformations. The crucial role of the tubulin superfamily in diverse cellular processes and the association of mutations with a broad [1 ] TUBA1A lissencephaly spectrum led us to hypothesize that mutations in other tubulin genes that are highly expressed during CNS [2 4 ] development might also result in malformations of cortical development. In a previous screen of agyria/pachygyria patients, we excluded the implication of , and . In this study we report the screening of 3 additional candidate tubulin genes ( TUBA1B TUBA1C TUBB3 [3 ] ) in patients with a wide range of cortical dysgeneses, including polymicrogyria (PMG) syndromes associated with epilepsy TUBB2A,B,C and/or neurodevelopmental delay (see Material and Methods section). Although no non-synonymous variations were found either in or in (see alignment in ), heterozygous missense mutations were found in ( ) in TUBB2A TUBB2C Supplementary Fig. 1 TUBB2B Fig. 1a four unrelated individuals and one fetus. All mutations, c.514T C (p.S172P), c.629T C (p.I210T), c.683T C (p.L228P), c.793T C > > > > (p.F265L) and c.935C T (p.T312M) affect residues that are rigidly conserved from yeast to human and reside in > Supplementary Fig. 2 exon 4 ( , ). Consistent with a origin of the mutations, none were found in the parents of affected Fig. 1a Table 1 de novo TUBB2B individuals or in 360 normal controls (see referenced polymorphisms in ). Brain MRI sequences revealed that all Supplementary Fig. 1 patients share the presence of a complex brain dysgenesis with bilateral, asymmetrical, and anteriorly predominant polymicrogyria (PMG), fusion of the caudate and putamen with internal capsule hypoplasia, corpus callosum agenesis or dysgenesis and, in most cases, cerebellar