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

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.
Aimee L Fenwick 1,  Maciej Kliszczak 2,  Fay Cooper 3,  Jennie Murray 3,  Luis Sanchez-Pulido 3,  Stephen R F Twigg 1,  Anne Goriely 1,  Simon J McGowan 4,  Kerry A Miller 1,  Indira B Taylor 1,  Clare Logan 3,  WGS500 Consortium,  Sevcan Bozdogan 5,  Sumita Danda 6,  Joanne Dixon 7,  Solaf M Elsayed 8,  Ezzat Elsobky 8,  Alice Gardham 9,  Mariette J V Hoffer 10,  Marije Koopmans 10,  Donna M McDonald-McGinn 11,  Gijs W E Santen 10,  Ravi Savarirayan 12,  Deepthi de Silva 13,  Olivier Vanakker 14,  Steven A Wall 15,  Louise C Wilson 9,  Ozge Ozalp Yuregir 16,  Elaine H Zackai 11,  Chris P Ponting 3,  Andrew P Jackson 3,  Andrew O M Wilkie 17,  Wojciech Niedzwiedz 18,  Louise S Bicknell 19
Affiliations

Affiliations

  • 1 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
  • 2 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
  • 3 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK.
  • 4 Computational Biology Research Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK.
  • 5 Department of Medical Genetics, Mersin University, Mersin, 33343 Cukurova, Turkey.
  • 6 Department of Clinical Genetics, Christian Medical College and Hospital, Vellore, Tamil Nadu 632004, India.
  • 7 Genetic Health Service NZ-South Island Hub, Christchurch Hospital, Christchurch, Canterbury 8140, New Zealand.
  • 8 Children's Hospital, Ain Shams University, Cairo 11566, Egypt.
  • 9 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street Hospital, London WC1N 3JH, UK.
  • 10 Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
  • 11 Clinical Genetics, The Children's Hospital of Philadelphia, 34th & Civic Center Boulevard, Philadelphia, PA 19104, USA.
  • 12 Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Melbourne, VIC 3052, Australia.
  • 13 Department of Physiology, Faculty of Medicine, University of Kelaniya, Ragama, Gampaha GQ 11010, Sri Lanka.
  • 14 Center for Medical Genetics, Ghent University Hospital, 9000 Ghent, Belgium.
  • 15 Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
  • 16 Genetic Diagnosis Center, Adana Numune Training and Research Hospital, Cukurova, Adana, 01170, Turkey.
  • 17 Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DS, UK; Craniofacial Unit, Department of Plastic and Reconstructive Surgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford OX3 9DU, UK.
  • 18 Department of Oncology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: [email protected].
  • 19 MRC Human Genetics Unit, IGMM, University of Edinburgh, Edinburgh EH4 2XU, UK; Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin, Otago 9016, New Zealand. Electronic address: [email protected].
PMID: 27374770 DOI: 10.1016/j.ajhg.2016.05.019
Abstract

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.

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