TUBB4B – Leber congenital amaurosis with early-onset deafness

TUBB4B encodes the β-4B tubulin isotype, a fundamental component of microtubule heterodimers. Pathogenic heterozygous variants in TUBB4B are associated with Leber congenital amaurosis with early-onset deafness (LCAEOD), an autosomal dominant syndrome marked by photoreceptor degeneration and sensorineural hearing loss.

Genetic evidence includes a multiplex family and three simplex case subjects harboring heterozygous Arg391 substitutions (4 probands) (PMID:29198720) and a de novo missense variant c.32A>G (p.Gln11Arg) in a single affected individual (PMID:37448631). All reported variants are missense changes clustering at key interface residues of β-tubulin.

Inheritance is autosomal dominant, with segregation demonstrated in one multiplex pedigree (≥3 additional affected relatives) and de novo occurrence. The variant spectrum comprises c.1171C>T (p.Arg391Cys) and c.1172G>A (p.Arg391His) at Arg391 and c.32A>G (p.Gln11Arg), underscoring a mutational hotspot within TUBB4B.

Functional assays in cultured cells expressing mutant TUBB4B revealed intact folding and heterodimer assembly but significantly dampened microtubule growth dynamics, consistent across FLAG‐tag overexpression and patient fibroblasts (PMID:29198720). Structural inspection highlights disrupted longitudinal αβ‐heterodimer interactions, providing a mechanistic link to microtubule instability.

Dominant-negative perturbation of microtubule stability impairs photoreceptor and cochlear cell maintenance, aligning with clinical early visual failure and hearing loss. This mechanism is further supported by structural modeling of the Gln11Arg substitution affecting transporter protein trafficking in renal epithelia, although renal phenotypes in the single case await further cohort validation.

In summary, strong genetic and moderate functional evidence support a pathogenic role for heterozygous TUBB4B variants in LCAEOD, enabling confident molecular diagnosis, genetic counseling, and potential development of microtubule-targeted therapies.

References

• Molecular genetics and metabolism reports • 2023 • Clinical, genetic, and structural characterization of a novel TUBB4B tubulinopathy. PMID:37448631
• American journal of human genetics • 2017 • Mutations in TUBB4B Cause a Distinctive Sensorineural Disease. PMID:29198720

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