title: Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy.
abstract: We have identified TUBGCP4 variants in individuals with autosomal-recessive microcephaly and chorioretinopathy. Whole-exome sequencing performed on one family with two affected siblings and independently on another family with one affected child revealed compound-heterozygous mutations in TUBGCP4. Subsequent Sanger sequencing was performed on a panel of individuals from 12 French families affected by microcephaly and ophthalmic manifestations, and one other individual was identified with compound-heterozygous mutations in TUBGCP4. One synonymous variant was common to all three families and was shown to induce exon skipping; the other mutations were frameshift mutations and a deletion. TUBGCP4 encodes γ-tubulin complex protein 4, a component belonging to the γ-tubulin ring complex (γ-TuRC) and known to regulate the nucleation and organization of microtubules. Functional analysis of individual fibroblasts disclosed reduced levels of the γ-TuRC, altered nucleation and organization of microtubules, abnormal nuclear shape, and aneuploidy. Moreover, zebrafish treated with morpholinos against tubgcp4 were found to have reduced head volume and eye developmental anomalies with chorioretinal dysplasia. In summary, the identification of TUBGCP4 mutations in individuals with microcephaly and a spectrum of anomalies in eye development, particularly photoreceptor anomalies, provides evidence of an important role for the γ-TuRC in brain and eye development.
authors: Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France.
authors: Sophie
authors: S
authors: Scheidecker
authors: Institut für Toxikologie und Genetik Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
authors: Christelle
authors: C
authors: Etard
authors: Centre de Biologie du Développement, Université Paul Sabatier, 31062 Toulouse, France.
authors: Laurence
authors: L
authors: Haren
authors: Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France.
authors: Corinne
authors: C
authors: Stoetzel
authors: Inherited Eye Diseases, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors: Sarah
authors: S
authors: Hull
authors: Inherited Eye Diseases, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
authors: Gavin
authors: G
authors: Arno
authors: UCL Genetics Institute, London WC1E 6BT, UK.
authors: Vincent
authors: V
authors: Plagnol
authors: Unité Fonctionnelle de Génétique Moléculaire, Département de Génétique, Hôpital Robert Debré, Centre Hospitalier Universitaire Paris, 75019 Paris, France.
authors: Séverine
authors: S
authors: Drunat
authors: Unité Fonctionnelle de Génétique Moléculaire, Département de Génétique, Hôpital Robert Debré, Centre Hospitalier Universitaire Paris, 75019 Paris, France.
authors: Sandrine
authors: S
authors: Passemard
authors: Département de Génétique Médicale, Centre Hospitalier Régional et Universitaire de Tours, 37044 Tours, France.
authors: Annick
authors: A
authors: Toutain
authors: Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France.
authors: Cathy
authors: C
authors: Obringer
authors: Service de Radiopédiatrie et Imagerie, Hôpitaux Universitaires de Strasbourg et Laboratoire ICube, UMR 7357, Fédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Centre National de la Recherche Scientifique, 67098 Strasbourg, France.
authors: Mériam
authors: M
authors: Koob
authors: Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France.
authors: Véronique
authors: V
authors: Geoffroy
authors: Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France.
authors: Vincent
authors: V
authors: Marion
authors: Institut für Toxikologie und Genetik Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
authors: Uwe
authors: U
authors: Strähle
authors: Human Genetics, Cardiovascular and Cell Sciences Institute, St. George's University of London, London SW17 0RE, UK.
authors: Pia
authors: P
authors: Ostergaard
authors: Unité Fonctionnelle de Génétique Moléculaire, Département de Génétique, Hôpital Robert Debré, Centre Hospitalier Universitaire Paris, 75019 Paris, France.
authors: Alain
authors: A
authors: Verloes
authors: Centre de Biologie du Développement, Université Paul Sabatier, 31062 Toulouse, France.
authors: Andreas
authors: A
authors: Merdes
authors: Inherited Eye Diseases, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK; Ophthalmology Department, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
authors: Anthony T
authors: AT
authors: Moore
authors: Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France; Centre de Référence National pour les Affections Rares en Génétique Ophtalmologique, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France. Electronic address: dollfus@unistra.fr.
authors: Hélène
authors: H
authors: Dollfus
mesh_terms: D001483:Base Sequence; D015862:Choroid Diseases / Q000235:genetics*; D059472:Exome / Q000235:genetics; D015785:Eye Diseases, Hereditary / Q000235:genetics*; D016368:Frameshift Mutation / Q000235:genetics; D005602:France; D040461:Gene Components; D006801:Humans; D008831:Microcephaly / Q000235:genetics*; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008870:Microtubules / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D010375:Pedigree; D012164:Retinal Diseases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014404:Tubulin / Q000378:metabolism*
chemical_list: D008869:Microtubule-Associated Proteins; C401398:TUBGCP4 protein, human; D014404:Tubulin