PUBLICATION
Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome
- Authors
- Bicknell, L.S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., Martin, C.A., Yeyati, P., Al Sanna, N., Bober, M., Johnson, D., Wise, C., Jackson, A.P., O'Driscoll, M., and Jeggo, P.A.
- ID
- ZDB-PUB-110317-7
- Date
- 2011
- Source
- Nature Genetics 43(4): 350-5 (Journal)
- Registered Authors
- Yeyati, Patricia
- Keywords
- none
- MeSH Terms
-
- Consanguinity
- Adolescent
- Polymorphism, Single Nucleotide
- Mutant Proteins/chemistry
- Mutant Proteins/genetics
- Micrognathism/genetics
- Models, Molecular
- Sequence Homology, Amino Acid
- Protein Structure, Tertiary
- Mutation, Missense*
- Microcephaly/genetics*
- Male
- Ear/abnormalities
- Female
- Zebrafish/embryology
- Zebrafish/genetics
- Animals
- Humans
- Base Sequence
- Patella/abnormalities
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Molecular Sequence Data
- Genome-Wide Association Study
- Growth Disorders/genetics
- Models, Genetic
- Origin Recognition Complex/chemistry
- Origin Recognition Complex/deficiency
- Origin Recognition Complex/genetics*
- Infant
- Child
- Child, Preschool
- S Phase/genetics
- Congenital Microtia
- Saudi Arabia
- Amino Acid Substitution
- Amino Acid Sequence
- DNA/genetics
- Dwarfism/genetics*
- Pedigree
- PubMed
- 21358633 Full text @ Nat. Genet.
- CTD
- 21358633
Citation
Bicknell, L.S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., Martin, C.A., Yeyati, P., Al Sanna, N., Bober, M., Johnson, D., Wise, C., Jackson, A.P., O'Driscoll, M., and Jeggo, P.A. (2011) Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature Genetics. 43(4):350-5.
Abstract
Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping