PUBLICATION
Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy
- Authors
- Martin, C.A., Ahmad, I., Klingseisen, A., Hussain, M.S., Bicknell, L.S., Leitch, A., Nürnberg, G., Toliat, M.R., Murray, J.E., Hunt, D., Khan, F., Ali, Z., Tinschert, S., Ding, J., Keith, C., Harley, M.E., Heyn, P., Müller, R., Hoffmann, I., Daire, V.C., Dollfus, H., Dupuis, L., Bashamboo, A., McElreavey, K., Kariminejad, A., Mendoza-Londono, R., Moore, A.T., Saggar, A., Schlechter, C., Weleber, R., Thiele, H., Altmüller, J., Höhne, W., Hurles, M.E., Noegel, A.A., Baig, S.M., Nürnberg, P., Jackson, A.P.
- ID
- ZDB-PUB-170214-276
- Date
- 2014
- Source
- Nature Genetics 46: 1283-92 (Journal)
- Registered Authors
- Keywords
- Cell biolog,y DNA sequencing, Neurodevelopmental disorders
- MeSH Terms
-
- Adolescent
- Adult
- Animals
- Centrioles/ultrastructure
- Child
- Child, Preschool
- Family Health
- Female
- Fibroblasts/metabolism
- Genotype
- Growth Disorders/genetics*
- HeLa Cells
- Humans
- In Situ Hybridization, Fluorescence
- Infant
- Male
- Microcephaly/genetics*
- Microsatellite Repeats
- Microtubule-Associated Proteins/genetics
- Mitosis
- Mutation*
- Pakistan
- Pedigree
- Phenotype
- Protein Serine-Threonine Kinases/genetics*
- Retinal Degeneration/genetics*
- Young Adult
- Zebrafish
- PubMed
- 25344692 Full text @ Nat. Genet.
Citation
Martin, C.A., Ahmad, I., Klingseisen, A., Hussain, M.S., Bicknell, L.S., Leitch, A., Nürnberg, G., Toliat, M.R., Murray, J.E., Hunt, D., Khan, F., Ali, Z., Tinschert, S., Ding, J., Keith, C., Harley, M.E., Heyn, P., Müller, R., Hoffmann, I., Daire, V.C., Dollfus, H., Dupuis, L., Bashamboo, A., McElreavey, K., Kariminejad, A., Mendoza-Londono, R., Moore, A.T., Saggar, A., Schlechter, C., Weleber, R., Thiele, H., Altmüller, J., Höhne, W., Hurles, M.E., Noegel, A.A., Baig, S.M., Nürnberg, P., Jackson, A.P. (2014) Mutations in PLK4, encoding a master regulator of centriole biogenesis, cause microcephaly, growth failure and retinopathy. Nature Genetics. 46:1283-92.
Abstract
Centrioles are essential for ciliogenesis. However, mutations in centriole biogenesis genes have been reported in primary microcephaly and Seckel syndrome, disorders without the hallmark clinical features of ciliopathies. Here we identify mutations in the genes encoding PLK4 kinase, a master regulator of centriole duplication, and its substrate TUBGCP6 in individuals with microcephalic primordial dwarfism and additional congenital anomalies, including retinopathy, thereby extending the human phenotypic spectrum associated with centriole dysfunction. Furthermore, we establish that different levels of impaired PLK4 activity result in growth and cilia phenotypes, providing a mechanism by which microcephaly disorders can occur with or without ciliopathic features.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping