Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome

Nat Genet. 2011 Feb 27;43(4):350-5. doi: 10.1038/ng.776.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Animals
  • Base Sequence
  • Child
  • Child, Preschool
  • Congenital Microtia
  • Consanguinity
  • DNA / genetics
  • Dwarfism / genetics*
  • Ear / abnormalities
  • Female
  • Genome-Wide Association Study
  • Growth Disorders / genetics
  • Humans
  • Infant
  • Male
  • Microcephaly / genetics*
  • Micrognathism / genetics
  • Models, Genetic
  • Models, Molecular
  • Molecular Sequence Data
  • Mutant Proteins / chemistry
  • Mutant Proteins / genetics
  • Mutation, Missense*
  • Origin Recognition Complex / chemistry
  • Origin Recognition Complex / deficiency
  • Origin Recognition Complex / genetics*
  • Patella / abnormalities
  • Pedigree
  • Polymorphism, Single Nucleotide
  • Protein Structure, Tertiary
  • S Phase / genetics
  • Saudi Arabia
  • Sequence Homology, Amino Acid
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish Proteins / deficiency
  • Zebrafish Proteins / genetics


  • Mutant Proteins
  • ORC1 protein, human
  • Origin Recognition Complex
  • Zebrafish Proteins
  • DNA

Supplementary concepts

  • Meier-Gorlin syndrome

Associated data

  • RefSeq/NM_004153
  • RefSeq/NM_199933