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Updated: Oct 16, 2025
In Vivo Functional Study of Disease-associated Rare Human Variants Using Drosophila
Published on: August 20, 2019
TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset
Mary C Whitman1,2, Brenda J Barry3,4, Caroline D Robson5,6
1Department of Ophthalmology, Boston Children's Hospital, Boston, MA, 02115, USA.
Abstract:
Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype-phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.
Insights
A novel TUBB3 gene variant, R262H, causes a rare neurological syndrome with distinct brain and congenital malformations. This condition affects multiple systems, including ocular, endocrine, and nervous systems, leading to developmental delays and neuropathy.
Area of Science:
- Neurogenetics
- Developmental Biology
- Molecular Medicine
Background:
- Microtubules, crucial for cell structure, are composed of alpha- and beta-tubulin heterodimers.
- Genetic variants in tubulin isoforms, particularly TUBB3, are linked to brain malformations and neurological disorders.
- Distinct genotype-phenotype correlations exist for TUBB3 mutations, affecting conditions like CFEOM3 and cortical development.
Purpose of the Study:
- To characterize a novel phenotype associated with a specific TUBB3 missense variant (c.785G>A; p.Arg262His).
- To delineate the clinical spectrum and neurological findings in individuals with the TUBB3 R262H syndrome.
- To compare the TUBB3 R262H syndrome with other known TUBB3-related disorders.
Main Methods:
- Clinical evaluation of fourteen individuals from thirteen families with the TUBB3 R262H variant.
- Detailed assessment of neurological, ophthalmological, and developmental phenotypes.
- Neuroimaging analysis to identify characteristic brain malformations.
Main Results:
- Identified a recurrent TUBB3:c.785G>A (p.Arg262His) variant in thirteen unrelated families, defining the TUBB3 R262H syndrome.
- Affected individuals exhibit ptosis, ophthalmoplegia, facial weakness, joint contractures, intellectual disability, gait disorders, Kallmann syndrome, and peripheral neuropathy.
- Consistent brain malformations include corpus callosum and anterior commissure hypoplasia, basal ganglia malformations, and absent olfactory bulbs.
Conclusions:
- The TUBB3 R262H syndrome represents a distinct neurodevelopmental disorder with a recognizable pattern of congenital anomalies and progressive neurological deficits.
- This syndrome can be differentiated from other TUBB3-related disorders, such as the E410K syndrome, by specific clinical features like joint contractures and basal ganglia malformations.
- The study highlights the critical role of TUBB3 in neuronal development and function, emphasizing the impact of specific missense variants on complex phenotypes.
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