Overlapping cortical malformations and mutations in TUBB2B and TUBA1A

Thomas D. Cushion, William B. Dobyns, Jonathan G.L. Mullins, Neil Stoodley, Seo Kyung Chung, Andrew E. Fry, Ute Hehr, Roxana Gunny, Arthur S. Aylsworth, Prab Prabhakar, Gökhan Uyanik, Julia Rankin, Mark I. Rees, Daniela T. Pilz

Research output: Contribution to journalArticlepeer-review

119 Scopus citations


Polymicrogyria and lissencephaly are causally heterogeneous disorders of cortical brain development, with distinct neuropathological and neuroimaging patterns. They can be associated with additional structural cerebral anomalies, and recurrent phenotypic patterns have led to identification of recognizable syndromes. The lissencephalies are usually single-gene disorders affecting neuronal migration during cerebral cortical development. Polymicrogyria has been associated with genetic and environmental causes and is considered a malformation secondary to abnormal post-migrational development. However, the aetiology in many individuals with these cortical malformations is still unknown. During the past few years, mutations in a number of neuron-specific α-and β-tubulin genes have been identified in both lissencephaly and polymicrogyria, usually associated with additional cerebral anomalies including callosal hypoplasia or agenesis, abnormal basal ganglia and cerebellar hypoplasia. The tubulin proteins form heterodimers that incorporate into microtubules, cytoskeletal structures essential for cell motility and function. In this study, we sequenced the TUBB2B and TUBA1A coding regions in 47 patients with a diagnosis of polymicrogyria and five with an atypical lissencephaly on neuroimaging. We identified four β-tubulin and two α-tubulin mutations in patients with a spectrum of cortical and extra-cortical anomalies. Dysmorphic basal ganglia with an abnormal internal capsule were the most consistent feature. One of the patients with a TUBB2B mutation had a lissencephalic phenotype, similar to that previously associated with a TUBA1A mutation. The remainder had a polymicrogyria-like cortical dysplasia, but the grey matter malformation was not typical of that seen in 'classical' polymicrogyria. We propose that the cortical malformations associated with these genes represent a recognizable tubulinopathy-associated spectrum that ranges from lissencephalic to polymicrogyric cortical dysplasias, suggesting shared pathogenic mechanisms in terms of microtubular function and interaction with microtubule-associated proteins.

Original languageEnglish (US)
Pages (from-to)536-548
Number of pages13
Issue number2
StatePublished - Feb 2013
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by the National Institute of Social Care and Health Research (NISCHR) as part of a PhD scholarship (M.I.R., T.D.C.); and the Wales Epilepsy Research Network (WERN) (M.I.R., D.T.P.).


  • corpus callosum
  • lissencephaly
  • neuronal migration
  • polymicrogyria
  • tubulinopathy


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