Poirier et al. (2013) reported 3 unrelated patients with complex cortical malformations. Two had a more severe disorder, with microcephaly (-5.5 SD and -4 SD, respectively), spastic tetraplegia, posterior agyria, frontal pachygyria, and a thick cortex. One had ... Poirier et al. (2013) reported 3 unrelated patients with complex cortical malformations. Two had a more severe disorder, with microcephaly (-5.5 SD and -4 SD, respectively), spastic tetraplegia, posterior agyria, frontal pachygyria, and a thick cortex. One had thin corpus callosum and 1 had thick and dysmorphic corpus callosum. They were bedridden with spastic tetraplegia at ages 21 years and 1.5 years, respectively. The third patient, who was 31 years of age, did not have microcephaly and had moderate intellectual disability. MRI showed posterior pachygyria, posterior subcortical band heterotopia, and thick and dysmorphic corpus callosum. The patient also had cataract. All patients had early-onset seizures.
In 3 unrelated patients with complex cortical malformations, Poirier et al. (2013) identified heterozygous mutations in the TUBG1 gene (191135.0001-191135.0003). Two of the mutations were confirmed to be de novo, whereas DNA from the third patient's father was ... In 3 unrelated patients with complex cortical malformations, Poirier et al. (2013) identified heterozygous mutations in the TUBG1 gene (191135.0001-191135.0003). Two of the mutations were confirmed to be de novo, whereas DNA from the third patient's father was unavailable. The first 2 mutations were found by whole-exome sequencing and were not present in several genomic databases, including dbSNP, 1000 Genomes, the Exome Variant Server, and a local Paris Descartes Bioinformatics platform database. The third mutation was found by screening 162 individuals with various malformations of cortical development for variants in the same gene. In vitro functional expression studies of some of the mutations suggested that they caused defects in mitotic microtubule organization. Knockdown of Tubg1 in mouse embryos altered cortical radial neuronal migration, with an arrest of migrating cells in the subventricular and intermediate zone and impaired migration to the cortical plate. Poirier et al. (2013) postulated a dominant-negative effect. The findings indicated that TUBG1 has a role in neuronal migration during corticogenesis, and extended the association between microtubule-based cellular processes and proper cortical development.