ClinVar

In a mother and her 2 daughters with complex cortical dysplasia with other brain malformations-7 (CDCBM7; 610031) manifest as diffuse symmetric polymicrogyria, originally reported by Flaherty et al. (2001), Cederquist et al. (2012) identified a heterozygous c.1261G-A transition in exon 4 of the TUBB2B gene, resulting in a glu421-to-lys (E421K) substitution at a highly conserved residue in the C-terminal H12 alpha-helix of the protein crucial for kinesin-microtubule interactions. The mutation was not present in the dbSNP, 1000 Genomes, or Exome Variant Server databases, and was not found in 336 control individuals. The patients had intellectual impairment and congenital fibrosis of the extraocular muscles associated with hypoplasia of the extraocular muscles apparent in brain MRI. Brain MRI also showed polymicrogyria, asymmetry of the basal ganglia and ventricles, and thin corpus callosum. Diffusion tensor imaging of both daughters showed abnormal intracortical homotopic connectivity in the corpus callosum. Transfection of the mutation into wildtype callosal projection neurons of embryonic mice caused a decrease in the ratio of contralateral to ipsilateral tracts, consistent with an error in axonal pathfinding and targeted innervation, but this was not secondary to cortical dysplasia. Overexpression of the E421K mutant protein perturbed the accuracy of both local and long-range projections. Mutant E421K was able to assemble into alpha-beta heterodimers, although with slightly less efficiency compared to wildtype, and the mutant protein incorporated into microtubule networks. Studies in yeast showed that the mutation affected microtubule dynamics in a dominant manner, causing increased overall stability, and also altered kinesin (KIP3; 610645) localization. The findings were consistent with primary axonal dysinnervation. Cederquist et al. (2012) noted that similar mutations in the TUBB3 gene (D417N; 602661.0004 and E410K; 602661.0005) cause CFEOM3A (600638); these mutations also alter microtubule dynamics and interactions with kinesin.