Search

One set of missense mutations in the neuron specific beta tubulin isotype 3 (TUBB3) has been reported to cause malformations of cortical development (MCD), while a second set has been reported to cause isolated or syndromic Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3). Because TUBB3 mutations reported to cause CFEOM had not been associated with cortical malformations, while mutations reported to cause MCD had not been associated with CFEOM or other forms of paralytic strabismus, it was hypothesized that each set of mutations might alter microtubule function differently. Here, however, we report two novel de novo heterozygous TUBB3 amino acid substitutions, G71R and G98S, in four patients with both MCD and syndromic CFEOM3. These patients present with moderately severe CFEOM3, nystagmus, torticollis, and developmental delay, and have intellectual and social disabilities. Neuroimaging reveals defective cortical gyration, as well as hypoplasia or agenesis of the corpus callosum and anterior commissure, malformations of hippocampi, thalami, basal ganglia and cerebella, and brainstem and cranial nerve hypoplasia. These new TUBB3 substitutions meld the two previously distinct TUBB3-associated phenotypes, and implicate similar microtubule dysfunction underlying both.

The distributions of excitatory and inhibitory synapses upon the dendritic arbor of a direction-selective retinal ganglion cell were compared by triple-labeling techniques. The dendrites were visualized by confocal microscopy after injection of Lucifer yellow. Excitatory inputs from bipolar cells were located by using antibodies against kinesin II, a component of synaptic ribbons. Inhibitory inputs were identified by antibodies against γ-aminobutyric acid-A receptors. The combined images were examined by visual inspection and by formal, automated analyses, in a search for anisotropies that might contribute to a directional preference of the ganglion cell. Within the limits of our analysis, none was found. If an anatomic specialization underlies direction selectivity, it appears to lie in the geometry and spatial positioning of the neurons afferent to the ganglion cell and/or the microcircuitry among its afferent synapses. J. Comp. Neurol. 449:195–205, 2002. © 2002 Wiley-Liss, Inc.