2. Academic Validation
  3. Mutations in TUBB4B Cause a Distinctive Sensorineural Disease

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

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].
PMID: 29198720 DOI: 10.1016/j.ajhg.2017.10.010
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.

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