Mutations in the Pre-Replication Complex cause Meier-Gorlin syndrome

Medical Research Council (MRC) Human Genetics Unit (HGU), Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
Nature Genetics (Impact Factor: 29.35). 02/2011; 43(4):356-9. DOI: 10.1038/ng.775
Source: PubMed


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 ears¹⁻³. 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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    • "However, point mutation in human (Y232S) demonstrates mild postnatal phenotype [Bicknell et al., 2011a; de Munnik et al., 2012], while the Drosophila Y225S MGS mutation shows no difference from lethal orc6 deletion. Importantly, human Orc6 is loosely associated with the core ORC [Vashee et al., 2001, 2003; Ranjan and Gossen, 2006], whereas Drosophila Orc6 associates with other ORC subunits more tightly [Gossen et al., 1995; Chesnokov et al., 1999, 2001]. "
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    ABSTRACT: Meier-Gorlin syndrome (MGS) is an autosomal recessive disorder characterized by microtia, primordial dwarfism, small ears, and skeletal abnormalities. Patients with MGS often carry mutations in the genes encoding the components of the pre-replicative complex such as Origin Recognition Complex (ORC) subunits Orc1, Orc4, Orc6, and helicase loaders Cdt1 and Cdc6. Orc6 is an important component of ORC and has functions in both DNA replication and cytokinesis. Mutation in conserved C-terminal motif of Orc6 associated with MGS impedes the interaction of Orc6 with core ORC. In order to study the effects of MGS mutation in an animal model system we introduced MGS mutation in Orc6 and established Drosophila model of MGS. Mutant flies die at third instar larval stage with abnormal chromosomes and DNA replication defects. The lethality can be rescued by elevated expression of mutant Orc6 protein. Rescued MGS flies are unable to fly and display multiple planar cell polarity defects. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 07/2015; DOI:10.1002/ajmg.a.37214 · 2.16 Impact Factor
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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.
    DNA repair 04/2014; 19(100). DOI:10.1016/j.dnarep.2014.03.012 · 3.11 Impact Factor
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    • "below the population mean) [Klingseisen and Jackson, 2011]. MPD represents a group of rare Mendelian disorders, with causative genes affecting cell cycle progression through roles in centriole duplication (CEP152, CENPJ) [Al-Dosari et al., 2010; Kalay et al., 2011], DNA replication (ORC1, ORC4, ORC6, CDC6, CDT1, MCM4) [Bicknell et al., 2011a; Bicknell et al., 2011b; Gineau et al., 2012; Hughes et al., 2012], ATR-dependent DNA damage response signaling and repair (PCNT, ATR, ATRIP, RBBP8) [O'Driscoll et al., 2003; Ogi et al., 2012; Qvist et al., 2011; Rauch et al., 2008] and mitotic spindle organization (PCNT) [Zimmerman et al., 2004]. "
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    ABSTRACT: Ligase IV syndrome is a rare differential diagnosis for Nijmegen Breakage syndrome owing to a shared predisposition to lympho-reticular malignancies, significant microcephaly and radiation hypersensitivity. Only 16 cases with mutations in LIG4 have been described to date with phenotypes varying from malignancy in developmentally normal individuals, to severe combined immunodeficiency and early mortality. Here we report the identification of biallelic truncating LIG4 mutations in 11 patients with microcephalic primordial dwarfism presenting with restricted prenatal growth and extreme postnatal global growth failure (average OFC -10.1 s.d., height -5.1 s.d.). Subsequently most patients developed thrombocytopenia and leucopenia later in childhood and many were found to have previously unrecognised immunodeficiency following molecular diagnosis. None have yet developed malignancy, though all patients tested had cellular radiosensitivity. A genotype:phenotype correlation was also noted with position of truncating mutations corresponding to disease severity. This work extends the phenotypic spectrum associated with LIG4 mutations, establishing that extreme growth retardation with microcephaly is a common presentation of bilallelic truncating mutations. Such growth failure is therefore sufficient to consider a diagnosis of LIG4 deficiency and early recognition of such cases is important as bone marrow failure, immunodeficiency and sometimes malignancy are long term sequelae of this disorder. This article is protected by copyright. All rights reserved.
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