학술논문
Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.
Document Type
Article
Author
Luscan, Romain; Mechaussier, Sabrina; Paul, Antoine; Tian, Guoling; Gérard, Xavier; Defoort-Dellhemmes, Sabine; Loundon, Natalie; Audo, Isabelle; Bonnin, Sophie; LeGargasson, Jean-François; Dumont, Julien; Goudin, Nicolas; Garfa-Traoré, Meriem; Bras, Marc; Pouliet, Aurore; Bessières, Bettina; Boddaert, Nathalie; Sahel, José-Alain; Lyonnet, Stanislas; Kaplan, Josseline
Source
Subject
*TUBULIN genetics
*BLINDNESS
*RETINAL diseases
*PHOTORECEPTORS
*MOSAICISM
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Language
ISSN
0002-9297
Abstract
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. [ABSTRACT FROM AUTHOR]