Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy

Am J Hum Genet. 2015 Apr 2;96(4):666-74. doi: 10.1016/j.ajhg.2015.02.011.

Sophie Scheidecker ¹, Christelle Etard ², Laurence Haren ³, Corinne Stoetzel ¹, Sarah Hull ⁴, Gavin Arno ⁴, Vincent Plagnol ⁵, Séverine Drunat ⁶, Sandrine Passemard ⁶, Annick Toutain ⁷, Cathy Obringer ¹, Mériam Koob ⁸, Véronique Geoffroy ¹, Vincent Marion ¹, Uwe Strähle ², Pia Ostergaard ⁹, Alain Verloes ⁶, Andreas Merdes ³, Anthony T Moore ¹⁰, Hélène Dollfus ¹¹

Affiliations

1 Medical Genetics Laboratory, INSERM U1112, Institute of Genetics and Medicine of Alsace, Strasbourg Medical School, University of Strasbourg, 67085 Strasbourg, France.
2 Institut für Toxikologie und Genetik Campus Nord, Karlsruher Institut für Technologie, Hermann-von-Helmholtz-Platz 1, 76344 Eggenstein-Leopoldshafen, Germany.
3 Centre de Biologie du Développement, Université Paul Sabatier, 31062 Toulouse, France.
4 Inherited Eye Diseases, UCL Institute of Ophthalmology, London EC1V 9EL, UK; Moorfields Eye Hospital, London EC1V 2PD, UK.
5 UCL Genetics Institute, London WC1E 6BT, UK.
6 Unité Fonctionnelle de Génétique Moléculaire, Département de Génétique, Hôpital Robert Debré, Centre Hospitalier Universitaire Paris, 75019 Paris, France.
7 Département de Génétique Médicale, Centre Hospitalier Régional et Universitaire de Tours, 37044 Tours, France.
8 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.
9 Human Genetics, Cardiovascular and Cell Sciences Institute, St. George's University of London, London SW17 0RE, UK.
10 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.
11 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: [email protected].

PMID: 25817018 DOI: 10.1016/j.ajhg.2015.02.011

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.

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