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

Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
Nature Genetics (Impact Factor: 29.35). 02/2011; 43(4):360-4. DOI: 10.1038/ng.777
Source: PubMed


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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Available from: Mark Elliott Samuels, Jun 25, 2014
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    • "In contrast to the phenotype of MCM hypomorphic mice, human patients with Meier Gorlin syndrome (MGS), a rare disorder linked to defective non-MCM pre-RC proteins (ORC1, ORC4, ORC6, CDT1, and CDC6) is characterized by primordial dwarfism, mild to severe microcephaly, and hypoplasia of the ear and patella [6,7,35]. Some of these defects have been suggested to result from cell-type specific proliferation defects during development. "
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    ABSTRACT: The ability of a eukaryotic cell to precisely and accurately replicate its DNA is crucial to maintain genome stability. Here we describe our current understanding of the process by which origins are licensed for DNA replication and review recent work suggesting that fork stalling has exerted a strong selective pressure on the positioning of licensed origins. In light of this, we discuss the complex and disparate phenotypes observed in mouse models and humans patients that arise due to defects in replication licensing proteins.
    Full-text · Article · Apr 2014 · DNA repair
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    • "Sequencing of the MGS patients identified mutations in ORC1, ORC4, ORC6, CDC6 and CDT1 genes [46,48,49]. In contrast with truncation and splicing mutations, site-specific missense mutations that result in amino acid residue substitutions are more dominant in MGS, including E127G and R105Q in Orc1, Y174C in Orc4, Y232S in Orc6, T323R in Cdc6 and R462Q in Cdt1 [48,50,51]. This is consistent with the essential cellular functions of DNA replication machinery, and is further suggestive of functional domains underlying these specific single mutations. "
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    ABSTRACT: The origin recognition complex (ORC) serves as the initiator for the assembly of the pre-replication complex and the subsequent DNA replication. Together with many of its non-replication functions, ORC is a pivotal regulator of various cellular processes. Notably, a number of reports connect ORC to numerous human diseases, including Meier-Gorlin syndrome, Epstein-Barr virus-infected diseases, American Trypanosomiasis, and African Trypanosomiasis. However, much of the underlying molecular mechanism remains unclear. In those genetic diseases, mutations in ORC alter its function and lead to the dysregulated phenotypes; whereas in some pathogen-induced symptoms, host ORC and archaeal-like ORC are exploited by these organisms to maintain their own genomes. In this review, I provide detailed examples of ORC-related human diseases, and summarize the current findings on how ORC is involved and/or dysregulated. I further discuss how these discoveries can be generalized as model systems, which can then be applied to elucidating other related diseases and revealing potential targets for developing effective therapies.
    Full-text · Article · May 2013 · Bioscience Reports
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    • "Recently, three studies reported that mutations in pre-RC proteins, including human Orc1, are associated with Meier-Gorlin syndrome, a form of microcephalic primordial dwarfism (Bicknell et al. 2011a,b; Guernsey et al. 2011; de Munnik et al. 2012). Of the mutations reported in human Orc1 in Meier-Gorlin syndrome, the three mutations (F89S, R105Q, and E127G) occurred within the CID that contains a bromo-associated homology (BAH) domain (Fig. 5A, top panel; Zhang et al. 2002; Kuo et al. 2012). "
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    ABSTRACT: Like DNA replication, centrosomes are licensed to duplicate once per cell division cycle to ensure genetic stability. In addition to regulating DNA replication, the Orc1 subunit of the human origin recognition complex controls centriole and centrosome copy number. Here we report that Orc1 harbors a PACT centrosome-targeting domain and a separate domain that differentially inhibits the protein kinase activities of Cyclin E-CDK2 and Cyclin A-CDK2. A cyclin-binding motif (Cy motif) is required for Orc1 to bind Cyclin A and inhibit Cyclin A-CDK2 kinase activity but has no effect on Cyclin E-CDK2 kinase activity. In contrast, Orc1 inhibition of Cyclin E-CDK2 kinase activity occurs by a different mechanism that is affected by Orc1 mutations identified in Meier-Gorlin syndrome patients. The cyclin/CDK2 kinase inhibitory domain of Orc1, when tethered to the PACT domain, localizes to centrosomes and blocks centrosome reduplication. Meier-Gorlin syndrome mutations that disrupt Cyclin E-CDK2 kinase inhibition also allow centrosome reduplication. Thus, Orc1 contains distinct domains that control centrosome copy number and DNA replication. We suggest that the Orc1 mutations present in some Meier-Gorlin syndrome patients contribute to the pronounced microcephaly and dwarfism observed in these individuals by altering centrosome duplication in addition to DNA replication defects.
    Full-text · Article · Aug 2012 · Genes & development
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