Cortical Dysplasia, Complex, With Other Brain Malformations 6

A number sign (#) is used with this entry because complex cortical dysplasia with other brain malformations-6 (CDCBM6) is caused by heterozygous mutation in the TUBB gene (191130) on chromosome 6p21.

For a discussion of genetic heterogeneity of CDCBM, see CDCBM1 (614039).

Clinical Features

Breuss et al. (2012) reported 3 unrelated children with severely delayed psychomotor development and microcephaly (range -2.5 to -4 SD) who were found to have multiple abnormalities on brain imaging. All had dysmorphic basal ganglia, 2 with white matter streaks; all had corpus callosum abnormalities (2 with partial agenesis) and cerebellar abnormalities. One patient also had complex cortical dysgenesis, with focal polymicrogyria and localized band heterotopia; this patient also had retinal dysplasia and microphthalmia. The family history of 1 patient revealed microcephaly without mental retardation.

Molecular Genetics

In 3 unrelated children with complex cortical dysplasia with other brain malformations-6 and microcephaly, Breuss et al. (2012) identified 3 different de novo heterozygous missense mutations in the TUBB gene (191130.0001-191130.0003). The gene was chosen for study because of its role in mouse neuronal development. In vitro and in vivo functional studies showed that the mutations affected the assembly of tubulin heterodimers in different ways and disrupted cerebral neurogenic division and/or migration. The findings suggested a loss of function, although a dominant-negative effect could not be ruled out. Breuss et al. (2012) noted that patients with TUBB mutations share structural brain abnormalities in common with other tubulinopathies resulting from mutations in genes encoding other tubulins, including TUBA1A (602529), TUBB2B (612850), and TUBB3 (602661).

Animal Model

Breuss et al. (2012) found that short hairpin RNA (shRNA) knockdown of Tubb in mice resulted in a perturbation of the cell cycle of neurogenic progenitors as well as an alteration in the position of migrating neurons. There was a decrease in neurons in the cortical plate and an accumulation of cells within the ventricular and intermediate zones.