Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
Luscan R, Mechaussier S, Paul A, Tian G, Gérard X, Defoort-Dellhemmes S, Loundon N, Audo I, Bonnin S, LeGargasson JF, Dumont J, Goudin N, Garfa-Traoré M, Bras M, Pouliet A, Bessières B, Boddaert N, Sahel JA, Lyonnet S, Kaplan J, Cowan NJ, Rozet JM, Marlin S, Perrault I.
Am. J. Hum. Genet.
2018 Jan 2
Pmid / DOI:
Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the β-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αβ-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αβ-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.