Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome
By L. Bicknell, Sarah A. Walker, Anna Klingseisen, T. Stiff, A. Leitch, Claudia Kerzendorfer, Carol-Anne Martin, P. Yeyati, Nouriya Al Sanna, M. Bober and 5 more. 2011
224 citations recorded by the source corpus.
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.
Subfields: Genetics, Molecular Biology, Rheumatology
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Citations in the corpus
- In silico protein interaction screening uncovers DONSON’s role in replication initiation (2023, background): “As replication licensing defects reduce cell proliferation during development ( 52 ), impaired CMG assembly could also limit embryonic cell divisions.”
- The expanding genetic and clinical landscape associated with Meier-Gorlin syndrome (2023, background): “Analysis of zebrafish models generated through morpholinos targeting orc1 showed significant decrease in overall growth, consistent with the MGORS phenotype [4].”
- Meier-Gorlin syndrome (2015, unknown): “One patient was described with short stature, but without microtia or patellar anomalies, indicating that the clinical phenotype might be more variable than previously suspected [3, 4].”
- Mechanisms and pathways of growth failure in primordial dwarfism. (2011, background): “MGS (ear, patella, and short stature syndrome) is a further distinct primordial dwarfism syndrome defined by absent/hypoplastic patellae and markedly small ears (Gorlin et al. 1975; Bongers et al. 2001).”