Journal Article

A mutational hotspot in TUBB2A associated with impaired heterodimer formation and severe brain developmental disorders

Accogli, Andrea, Di Pasquale, Gabriele, Salpietro, Vincenzo, Soler, Miguel A., Di Cataldo, Carola P., Comisi, Francesco F., Delvecchio, Maurizio, Nizon, Mathilde, Falsaperla, Raffaele, Di Rosa, Gabriella, Colella, Jacopo, Cecchetti, Corrado, Fortuna, Sara, Nardello, Rosaria, Mizrahi-Powell, Emma, Cognè, Benjamin, Vittori, Alessandro, Severino, Mariasavina, Pavone, Piero, Turchetti, Valentina, Mangano, Giuseppe D., Giliberti, Alessandra, Evrony, Gilad D.

2025

Overview

Microtubules are essential components of the neuronal cytoskeleton. The - and -tubulins, variably expressed in the central nervous system, play key roles in neurogenesis and brain development. Pathogenic variants in have recently been identified as an ultra-rare cause of pediatric neurodevelopmental disorders (NDDs). However, the neurological and behavioral manifestations, genotype-phenotype correlations, and underlying disease mechanisms remain poorly understood due to the limited number of reported families. We describe a cohort of families presenting with microcephaly, global developmental delay, speech impairment, seizures and/or EEG abnormalities, movement disorders and severe behavioral disorders. Clinical assessments and brain imaging studies were conducted over a 10-year follow-up period. Genetic analysis was performed via whole-exome sequencing (WES), and structural modeling was used to investigate the functional impact of the identified variants. WES revealed a novel recurrent heterozygous pathogenic variant in (NM_001069.3:c.1172G > A; NP_001060.1:p.Arg391His), identified as the cause of disease in multiple affected individuals from unrelated families. Comparative analysis with previously reported variants confirmed that this novel recurrent mutation affects a highly conserved Arg391 residue within the longitudinal E-site heterodimer interface. Computational modeling demonstrated that the variant disrupts / -tubulin heterodimer formation, impairing binding stability at this critical interaction site. Our findings expand the phenotypic and genotypic spectrum of -related disorders and identify Arg391 as a mutational hotspot linked to severe brain developmental disorders due to aberrant tubulin dynamics, highlighting the disruption of the / -tubulin heterodimer formation as the disease mechanism associated to this novel hotspot variant. These results provide new insights into disease mechanisms and offer a foundation for potential future therapeutic approaches aimed at stabilizing / -tubulin interactions.

• Publisher: Frontiers Media S.A
• Subject: behavioral disorders / intellectual disability / microcephaly / neurodevelopmental disorders / TUBB2A / tubulinopathies