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

Abstract

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. Here we report de novo mutations in a beta-tubulin gene, TUBB2B, in four individuals and a 27-gestational-week fetus with bilateral asymmetrical polymicrogyria. 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 TUBB2B is required for neuronal migration. We also show that two disease-associated mutations lead to impaired formation of tubulin heterodimers. These observations, together with previous data, show that disruption of microtubule-based processes underlies a large spectrum of neuronal migration disorders that includes not only lissencephaly and pachygyria, but also polymicrogyria malformations.

Symmetric polymicrogyria and pachygyria associated with TUBB2B gene mutations

“…Figure 2 Cartoon representation of the human a-tubulin/b-tubulin dimer. In blue, the mutations identified in the present study; in green, the mutations identified by Jaglin et al 5 The Asn256 residue, located in the b-tubulin H8 helix, is involved in the formation of the longitudinal contacts between a and b-tubulin at both the intradimer and interdimer interface. The Asp417 residue is located in the b-tubulin H12 helix, which represents a major site for interaction with motor proteins.…”

“…12 Mutations of GPR56 have been reported in patients with bilateral frontoparietal polymicrogyria, 4 a recessive disorder with MRI characteristics resembling those of the cobblestone malformations spectrum. 2 TUBB2B mutations have previously been associated with anteriorly predominant asymmetrical polymicrogyria, 5 more severe in the fronto-parietal areas, and involving the perisylvian region with left-sided predominance. Jaglin et al 5 demonstrated that TUBB2B mutations can lead to overmigration of MAP2-positive neurons through breaches in the pial basement membrane, leading to cobblestone-like structural changes.…”

“…10 De novo TUBB2B mutations, all missense, have been identified in four patients and in one fetus with bilateral, asymmetrical and anteriorly predominant polymicrogyria. 5 Neuropathological studies in fetuses with TUBA1A and TUBB2B mutations suggest that tubulin-related cortical dysgeneses are neuronal migration disorders with mislocation of developing neurons within the cortex. 7 Functional studies suggest that abnormal neuronal migration would result from defective interactions in the tubulin heterodimer assembly and altered three-dimensional conformation of the tubulins, with compromised interaction with microtubule-associated proteins or microtubule motors.…”

“…Mutations in TUBB2B have been reported in four patients and in one fetus with complex brain dysgenesis with asymmetrical, anteriorly predominant polymicrogyria. 5 We performed TUBB2B mutation analysis in 128 patients in whom brain MRI had detected a spectrum of malformations of cortical development including polymicrogyria or pachygyria, to investigate how common TUBB2B mutations are in this spectrum of malformations and whether previously suggested imaging criteria need to be expanded. …”

Expanding the spectrum of TUBA1A-related cortical dysgenesis to Polymicrogyria

“…To some extent, TUBA1A-related PMG shares some common features with PMG related to TUBB2B, a beta tubulin found to be involved in PMG. 10,25 In both conditions, large and dysmorphic basal ganglia, a hypoplastic brainstem and cerebellar hypoplasia are the hallmarks of tubulin-related cortical dysgenesis. However, TUBB2B-related PMG differs from TUBA1A-related PMG by its more diffuse presentation and its topography most prominent in anterior regions, that is, fronto-parieto temporal PMG.…”