Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome

Louise S. Bicknell, Sarah Walker, Anna Klingseisen, Tom Stiff, Andrea Leitch, Claudia Kerzendorfer, Carol Anne Martin, Patricia Yeyati, Nouriya Al Sanna, Michael Bober, Diana Johnson, Carol Wise, Andrew P. Jackson, Mark O'Driscoll, Penny A. Jeggo

Research output: Contribution to journalArticle

138 Scopus citations

Abstract

Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.

Original languageEnglish (US)
Pages (from-to)350-356
Number of pages7
JournalNature genetics
Volume43
Issue number4
DOIs
StatePublished - Feb 2011

ASJC Scopus subject areas

  • Genetics

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    Bicknell, L. S., Walker, S., Klingseisen, A., Stiff, T., Leitch, A., Kerzendorfer, C., Martin, C. A., Yeyati, P., Al Sanna, N., Bober, M., Johnson, D., Wise, C., Jackson, A. P., O'Driscoll, M., & Jeggo, P. A. (2011). Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. Nature genetics, 43(4), 350-356. https://doi.org/10.1038/ng.776