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

Studies into disorders of extreme growth failure (for example, Seckel syndromeand Majewski osteodysplastic primordial dwarfismtype II) have implicated fundamental cellular processes of DNA damage response signaling and centrosomefunction in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfismresembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1functions including pre-replicative complexformation and origin activation. ORC1deficiency perturbs S-phaseentry and S-phaseprogression. Additionally, we show that Orc1depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1mutations 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 dwarfismand show a surprising but important developmental impact of impaired origin licensing.