PUBLICATION
Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy
- Authors
- 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.
- ID
- ZDB-PUB-150331-15
- Date
- 2015
- Source
- American journal of human genetics 96(4): 666-74 (Journal)
- Registered Authors
- Etard, Christelle, Strähle, Uwe
- Keywords
- none
- MeSH Terms
-
- 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
- 25817018 Full text @ Am. J. Hum. Genet.
Citation
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. (2015) Mutations in TUBGCP4 Alter Microtubule Organization via the γ-Tubulin Ring Complex in Autosomal-Recessive Microcephaly with Chorioretinopathy. American journal of human genetics. 96(4):666-74.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping