Mutations in TUBB4B Cause a Distinctive Sensorineural Disease PMID: 29198720

RQC and Longevity Regulation

2026-09-03

Mutations in TUBB4B Cause a Distinctive Sensorineural Disease

Am J Hum Genet. 2017 Dec 7;101(6):1006-1012. doi: 10.1016/j.ajhg.2017.10.010.

Romain Luscan ¹ , Sabrina Mechaussier ² , Antoine Paul ¹ , Guoling Tian ³ , Xavier Gérard ² , Sabine Defoort-Dellhemmes ⁴ , Natalie Loundon ⁵ , Isabelle Audo ⁶ , Sophie Bonnin ⁷ , Jean-François LeGargasson ⁸ , Julien Dumont ⁹ , Nicolas Goudin ¹⁰ , Meriem Garfa-Traoré ¹⁰ , Marc Bras ¹¹ , Aurore Pouliet ¹² , Bettina Bessières ¹³ , Nathalie Boddaert ¹⁴ , José-Alain Sahel ⁶ , Stanislas Lyonnet ¹ , Josseline Kaplan ² , Nicholas J Cowan ³ , Jean-Michel Rozet ¹⁵ , Sandrine Marlin ¹⁶ , Isabelle Perrault ²

Affiliations

1. Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
2. Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.
3. Department of Biochemistry & Molecular Pharmacology, NYU Langone Medical Center, New York, NY 10016, USA.
4. Service d'Exploration de la Vision et Neuro-ophtalmologie, Pôle d'Imagerie et Explorations Fonctionnelles, CHRU de Lille, Hôpital Roger Salengro, 59000 Lille, France.
5. Pediatric ENT Department, Hôpital Necker-Enfants Malades, APHP and Paris Descartes University, 75015 Paris, France.
6. Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, 75012 Paris, France.
7. Ophthalmology Department, Hôpital Lariboisière, APHP and Paris Diderot University, 75010 Paris, France.
8. Visual Exploration Department, Hôpital Lariboisière, APHP, Paris, Diderot University, 75010 Paris, France.
9. Cell Division and Reproduction, Institut Jacques Monod, CNRS, University Paris Diderot, 75013 Paris, France.
10. Cell Imaging Core Facility of the Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633 Imagine and Paris Descartes University, 75015 Paris, France.
11. Bioinformatics Platform, Imagine and Paris Descartes University, 75015 Paris, France.
12. Genomics Platform, Imagine and Paris Descartes University, 75015 Paris, France.
13. Unité d'Embryo-foetopathologie, Hôpital Necker-Enfants Malades, APHP and Paris Descartes University, 75015 Paris, France.
14. Department of Pediatric Radiology, Hôpital Necker-Enfants Malades, APHP, Paris, Descartes University, 75015 Paris, France.
15. Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France. Electronic address: [email protected].
16. Laboratory of Embryology and Genetics of Human Malformation, INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France; Centre de Référence des Surdités Génétiques, Genetic Department, Hôpital Necker-Enfants Malades, APHP and Paris Descartes University, 75015 Paris, France. Electronic address: [email protected].

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.

Keywords

Leber congenital amaurosis; TUBB4B; abnormal dynamics of microtubule growth; de novo mutations; dominant mutations; early-onset sensorineural hearing loss; mosaicism; retino-cochlear tubulinopathy.