Mutations in CDC45, Encoding an Essential Component of the Pre-initiation Complex, Cause Meier-Gorlin Syndrome and Craniosynostosis

Am J Hum Genet. 2016 Jul 7;99(1):125-38. doi: 10.1016/j.ajhg.2016.05.019. Epub 2016 Jun 30.


DNA replication precisely duplicates the genome to ensure stable inheritance of genetic information. Impaired licensing of origins of replication during the G1 phase of the cell cycle has been implicated in Meier-Gorlin syndrome (MGS), a disorder defined by the triad of short stature, microtia, and a/hypoplastic patellae. Biallelic partial loss-of-function mutations in multiple components of the pre-replication complex (preRC; ORC1, ORC4, ORC6, CDT1, or CDC6) as well as de novo stabilizing mutations in the licensing inhibitor, GMNN, cause MGS. Here we report the identification of mutations in CDC45 in 15 affected individuals from 12 families with MGS and/or craniosynostosis. CDC45 encodes a component of both the pre-initiation (preIC) and CMG helicase complexes, required for initiation of DNA replication origin firing and ongoing DNA synthesis during S-phase itself, respectively, and hence is functionally distinct from previously identified MGS-associated genes. The phenotypes of affected individuals range from syndromic coronal craniosynostosis to severe growth restriction, fulfilling diagnostic criteria for Meier-Gorlin syndrome. All mutations identified were biallelic and included synonymous mutations altering splicing of physiological CDC45 transcripts, as well as amino acid substitutions expected to result in partial loss of function. Functionally, mutations reduce levels of full-length transcripts and protein in subject cells, consistent with partial loss of CDC45 function and a predicted limited rate of DNA replication and cell proliferation. Our findings therefore implicate the preIC as an additional protein complex involved in the etiology of MGS and connect the core cellular machinery of genome replication with growth, chondrogenesis, and cranial suture homeostasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Alternative Splicing / genetics
  • Amino Acid Sequence
  • Amnion / cytology
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / deficiency
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism
  • Cell Line
  • Cells, Cultured
  • Child
  • Child, Preschool
  • Congenital Microtia / genetics*
  • Craniosynostoses / genetics*
  • DNA Mutational Analysis
  • DNA Replication
  • Exome / genetics
  • Exons / genetics
  • Female
  • Genetic Association Studies
  • Growth Disorders / genetics*
  • Humans
  • Male
  • Micrognathism / genetics*
  • Models, Molecular
  • Mutation*
  • Patella / abnormalities*
  • Protein Conformation
  • Syndrome
  • Young Adult


  • CDC45 protein, human
  • Cell Cycle Proteins

Supplementary concepts

  • Meier-Gorlin syndrome