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
  • Models, Molecular
  • Infant
  • Animals
  • Origin Recognition Complex/chemistry
  • Origin Recognition Complex/deficiency
  • Origin Recognition Complex/genetics*
  • Child, Preschool
  • Ear/abnormalities
  • Humans
  • Mutation, Missense*
  • Sequence Homology, Amino Acid
  • Congenital Microtia
  • Female
  • Base Sequence
  • Consanguinity
  • Polymorphism, Single Nucleotide
  • Mutant Proteins/chemistry
  • Mutant Proteins/genetics
  • Micrognathism/genetics
  • Models, Genetic
  • S Phase/genetics
  • Protein Structure, Tertiary
  • Amino Acid Substitution
  • Growth Disorders/genetics
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Patella/abnormalities
  • Genome-Wide Association Study
  • Male
  • Microcephaly/genetics*
  • Saudi Arabia
  • Dwarfism/genetics*
  • Child
  • Adolescent
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Molecular Sequence Data
  • Amino Acid Sequence
  • DNA/genetics
  • Pedigree
PubMed
21358633 Full text @ Nat. Genet.
CTD
21358633
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
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping