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

Détails

ID Serval
serval:BIB_AAAFBFDC2E6D
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Mutations in TUBGCP4 alter microtubule organization via the γ-tubulin ring complex in autosomal-recessive microcephaly with chorioretinopathy.
Périodique
American journal of human genetics
Auteur⸱e⸱s
Scheidecker S., Etard C., Haren L., Stoetzel C., Hull S., Arno G., Plagnol V., Drunat S., Passemard S., Toutain A., Obringer C., Koob M., Geoffroy V., Marion V., Strähle U., Ostergaard P., Verloes A., Merdes A., Moore A.T., Dollfus H.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
02/04/2015
Peer-reviewed
Oui
Volume
96
Numéro
4
Pages
666-674
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.

Mots-clé
Base Sequence, Choroid Diseases/genetics, Exome/genetics, Eye Diseases, Hereditary/genetics, Frameshift Mutation/genetics, France, Gene Components, Humans, Microcephaly/genetics, Microtubule-Associated Proteins/genetics, Microtubules/genetics, Microtubules/metabolism, Molecular Sequence Data, Pedigree, Retinal Diseases/genetics, Sequence Analysis, DNA, Tubulin/metabolism
Pubmed
Web of science
Open Access
Oui
Création de la notice
28/08/2017 13:47
Dernière modification de la notice
20/08/2019 15:14
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