Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.
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Foremost we thank the families who generously contributed their time and material to this research study. Thanks to B. McConkey for suggestions regarding the ORC4 structure. D.L.G. and M.E.S. were supported by Genome Canada, Genome Atlantic, Nova Scotia Health Research Foundation, Nova Scotia Research and Innovation Trust, IWK Health Centre Foundation, Dalhousie Medical Research Fund and Capital Health Research Fund. M.E.S. was supported by the Centre de Recherche du CHU Ste-Justine. J.L.M. is a senior scientist of the Fonds pour la Recherche en Santé du Québec and was supported by an operating grant from the Canadian Institutes of Health Research. C.R.M. is supported by an operating grant from the Canadian Institutes of Health Research and the Canada Research Chairs fund. M.A.L. is supported by the Nova Scotia Health Research Foundation.
The authors declare no competing financial interests.
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Guernsey, D., Matsuoka, M., Jiang, H. et al. Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome. Nat Genet 43, 360–364 (2011). https://doi.org/10.1038/ng.777
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