Two unique TUBB3 mutations cause both CFEOM3 and malformations of cortical development

Area of Science:

• Neuroscience
• Genetics
• Developmental Biology

Background:

• Missense mutations in the beta tubulin isotype 3 (TUBB3) gene have been linked to distinct neurological conditions: malformations of cortical development (MCD) and Congenital Fibrosis of the Extraocular Muscles type 3 (CFEOM3).
• Previously, it was hypothesized that different sets of TUBB3 mutations might affect microtubule function uniquely, leading to these separate phenotypes.

Observation:

• This study reports two novel de novo heterozygous TUBB3 substitutions (G71R and G98S) in four patients exhibiting both MCD and syndromic CFEOM3.
• Patients presented with moderate to severe CFEOM3, nystagmus, torticollis, developmental delay, intellectual disability, and social deficits.

Findings:

• Neuroimaging revealed significant brain abnormalities, including defective cortical gyration, corpus callosum and anterior commissure hypoplasia/agenesis, and malformations of the hippocampi, thalami, basal ganglia, cerebella, brainstem, and cranial nerves.
• These novel TUBB3 substitutions bridge the previously distinct phenotypic categories of MCD and CFEOM3.
• The findings implicate a shared underlying microtubule dysfunction in both conditions.

Implications:

• These discoveries suggest that TUBB3 mutations can lead to a combined spectrum of neurological defects, challenging the notion of distinct disease mechanisms.
• Understanding the shared microtubule dysfunction offers new avenues for research into the pathogenesis of both CFEOM3 and MCD.
• This research highlights the critical role of TUBB3 in both ocular motor development and cortical formation.