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Mutations in the pre-replication complex cause Meier-Gorlin syndrome

Abstract

Meier-Gorlin syndrome (ear, patella and short-stature syndrome) is an autosomal recessive primordial dwarfism syndrome characterized by absent or hypoplastic patellae and markedly small ears1,2,3. Both pre- and post-natal growth are impaired in this disorder, and although microcephaly is often evident, intellect is usually normal in this syndrome. We report here that individuals with this disorder show marked locus heterogeneity, and we identify mutations in five separate genes: ORC1, ORC4, ORC6, CDT1 and CDC6. All of these genes encode components of the pre-replication complex, implicating defects in replication licensing as the cause of a genetic syndrome with distinct developmental abnormalities.

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Figure 1: The pre-replication complex and Meier-Gorlin syndrome.
Figure 2: Pre-replication complex proteins mutated in Meier-Gorlin syndrome.

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References

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Acknowledgements

We thank the subjects and their families for participation in this study and all clinicians for contributing samples not included in this manuscript. Also the late Robert J. Gorlin for contributing individual P3 to the study; E.S. Gray for pathology; M. Ansari, S. McKay, S.D. van der Velde-Visser, T.H. Merkx, S. Devroy and the MRC HGU core sequencing service for advice and technical support; E. Maher and colleagues for cytogenetic advice and assistance; and V. van Heyningen, N. Hastie, D. Fitzpatrick, I. Jackson and J. Blow for discussions and comments. This work was supported by funding from the MRC and Lister Institute of Preventative Medicine. A.P.J. is an MRC Senior Clinical Fellow and Lister Institute Prize fellow.

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Authors

Contributions

L.S.B. performed microsatellite genotyping. L.S.B., S.B. and J.S. performed mutation screening of cases and controls with the help of A.L., E.M.H.F.B., L.H.H., H.v.B. and N.V.A.M.K. M.E.H. performed chromosome breakage analysis. E.M.H.F.B. and A.P.J. clinically characterized the Meier-Gorlin syndrome cases and performed review of phenotypes and sample collection. S.A., J.Y.A.-A., M.B., P.A.J.B., H.v.B., J.D., A.Y.E., M.F., A.F., N.K., N.V.A.M.K., J.M., J.M.O., P.S., A.R., I.K.T., A.T., C.A.W. and M.W. contributed clinical cases and clinical data for the study. A.P.J. and L.S.B. wrote the paper with E.M.H.F.B.

Corresponding authors

Correspondence to Ernie M H F Bongers or Andrew P Jackson.

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The authors declare no competing financial interests.

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Supplementary Note, Supplementary Figure 1 and Supplementary Tables 1 and 2. (PDF 924 kb)

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Bicknell, L., Bongers, E., Leitch, A. et al. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nat Genet 43, 356–359 (2011). https://doi.org/10.1038/ng.775

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