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Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome

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Abstract

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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Figure 1: Families with Meier-Gorlin syndrome and phenotype.
Figure 2: Yeast analysis of the ORC4 missense mutation.

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NCBI Reference Sequence

References

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Acknowledgements

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.

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Authors

Contributions

D.L.G. supervised molecular studies and participated in manuscript preparation. M.M. performed molecular studies. H.J. performed statistical genetic and bioinformatic analyses. S.E. performed molecular studies. C.M. participated in clinical ascertainment and sample collection. M.N. performed molecular studies. S. Perry performed statistical genetic and bioinformatic analyses. M.F. participated in clinical ascertainment and sample collection. M. LeBlanc performed functional studies in yeast. J.P. performed molecular studies. L.P. performed molecular studies. A.L.R. and A.T. participated in clinical ascertainment and sample collection. A.O. participated in clinical ascertainment. C.R.M. supervised functional studies in yeast and participated in manuscript preparation. J.L.M., C.D., S.L., D.W.S. and S. Parkash performed clinical ascertainment and phenotyping studies and participated in manuscript preparation. M. Ludman helped supervise clinical ascertainment. D.L.S. supervised and performed clinical ascertainment and phenotyping studies and participated in manuscript preparation. M.E.S. supervised all aspects of the project and participated in manuscript preparation.

Corresponding author

Correspondence to Mark E Samuels.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Figures 1–7 and Supplementary Tables 1 and 2. (PDF 5874 kb)

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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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