FB2026_01 , released March 12, 2026
FB2026_01 , released March 12, 2026
Human Disease Model Report: Meier-Gorlin syndrome 2
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General Information
Name
Meier-Gorlin syndrome 2
FlyBase ID
FBhh0001205
Disease Ontology Term
Parent Disease
OMIM
MEIER-GORLIN SYNDROME 2; MGORS2
Overview

This report describes Meier-Gorlin syndrome 2, which shows autosomal recessive inheritance. The human gene implicated in this disease is ORC4, an origin replication complex member. There is a single high-ranking ortholog of ORC4 in Drosophila, Orc4, a member of the origin replication complex (FBgg0000510). Several alleles have been generated for Orc4, including RNAi targeting constructs, overexpression constructs, null mutants, hypomorphs, and alleles generated by insertional mutagenesis.

The human gene ORC4 has not been introduced into flies.

While Orc4 null mutations are lethal, the Orc4p.Tyr174Cys mutants (made to correspond to a known MGS-associated mutation in humans) are hypomorphs with tissue-specific defects, including several bristle defects. Orc4p.Tyr174Cys flies are female sterile, with egg chambers that have too few nurse cells, and follicle cells that fail to amplify chorion genes.

[updated Mar. 2020 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: Meier-Gorlin syndrome
Symptoms and phenotype

The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall, 2003; pubmed:14564153). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011; pubmed:21358632). [from MIM:224690; 2018.09.26]

(OMIM, 2013-)
Specific Disease Summary: Meier-Gorlin syndrome 2
OMIM report

[MEIER-GORLIN SYNDROME 2; MGORS2](https://omim.org/entry/613800)

Human gene(s) implicated

[ORIGIN RECOGNITION COMPLEX, SUBUNIT 4; ORC4](https://omim.org/entry/603056)

Symptoms and phenotype

Individuals with MGS present with several tissue-specific developmental defects, including primordial dwarfism, small or missing patella, and small ears. A significant number of patients also present with microcephaly, although typically have normal cognitive function. (From McDaniel et al. 2020 and references therein, FBrf0244772.)

(FlyBase Curators, 2013-)

The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (summary by Shalev and Hall 2003, pubmed:14564153). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al. 2011, pubmed:21358632). [from MIM:224690, 2020.03.06]

(OMIM, 2013-)
Genetics

Genes encoding members of the origin recognition complex (ORC) and additional proteins essential for DNA replication (CDC6, CDT1, GMNN, CDC45, MCM5, and DONSON) are mutated in individuals diagnosed with MGS. (From McDaniel et al. 2020, FBrf0244772.)

(FlyBase Curators, 2013-)

Bicknell et al. 2011 (pubmed:21358632) analyzed the ORC4 gene in patients with an established diagnosis of Meier-Gorlin syndrome and identified homozygosity for a missense mutation (Y174C; 603056.0001) in the monozygotic twin sisters previously reported by Bongers et al. 2001 (pubmed:11477602). Compound heterozygosity for Y174C and a frameshift mutation was also identified in an unrelated 23-year-old American woman with Meier-Gorlin syndrome. In 2 patients with Meier-Gorlin syndrome mapping to chromosome 2, Guernsey et al. 2011 (pubmed:21358631) independently identified homozygosity for the Y174C mutation in the ORC4 gene, and in 2 more MGS patients, they identified compound heterozygosity for the Y174C mutation and another mutation in the ORC4 gene. [from MIM:613800, 2020.03.06]

(OMIM, 2013-)
Cellular phenotype and pathology
Molecular information

In G1 phase, origins are selected by the binding of the origin recognition complex (ORC) comprised of six subunits (Orc1, Orc2, Orc3, Orc4, Orc5, and Orc6). ORC recruits Cdc6 and together this complex recruits the Cdt1 chaperone bound to the MCM hexamer, the core component of the replicative helicase. In an ATP-dependent process, an MCM complex, comprised of two head-to-head hexamers, assembles onto the double-stranded origin DNA, "licensing" the origin. (From McDaniel et al. 2020 and references therein, FBrf0244772.)

(FlyBase Curators, 2013-)
External links
Disease synonyms
MGS
MGS2
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    Symbol / Name
    ORC4; origin recognition complex subunit 4
    D. melanogaster ortholog (based on DIOPT)
    Dmel\Orc4
    (DIOPT, 2013-)
    Comments on ortholog(s)

    One to one: one human gene to one Drosophila gene.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Dmel\Orc4
      Gene Snapshot
      Origin recognition complex subunit 4 (Orc4) encodes is a subunit of the hetero-hexameric origin recognition complex (ORC). The ORC binds to origins of DNA replication and scaffolds assembly of a pre-replicative complex, which is required for the initiation of DNA replication. At other loci, the ORC is required for heterochromatin formation. [Date last reviewed: 2019-03-14]
      Molecular function (GO)
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      Single, high-scoring ortholog of human ORC4.

      Orthologs and Alignments from DRSC
      DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
      H. sapiens (Human)
      Other Genes Used: Viral, Bacterial, Synthetic (0)
        Summary of Physical Interactions (10 groups)
        Orc4
        protein-protein
        Interacting group
        Assay
        References
        Orc4 - Cdc6
        pull down, molecular weight estimation by staining, electron microscopy
        (Schmidt and Bleichert, 2020, Bleichert et al., 2018)
        Orc4 - e(y)2
        two hybrid, anti bait coimmunoprecipitation, western blot, peptide massfingerprinting
        (Maksimenko et al., 2018, Kopytova et al., 2016)
        Orc4 - Orc1
        electron microscopy, x-ray crystallography, pull down, autoradiography, molecular weight estimation by staining, cross-linking study, Identification by mass spectrometry
        (Schmidt and Bleichert, 2020, Bleichert et al., 2018, Bleichert et al., 2015, Bleichert et al., 2013)
        Orc4 - Orc2
        electron microscopy, cross-linking study, Identification by mass spectrometry, pull down, molecular weight estimation by staining, autoradiography, anti bait coimmunoprecipitation, western blot, x-ray crystallography
        (Schmidt and Bleichert, 2020, Bleichert et al., 2018, Kopytova et al., 2016, Bleichert et al., 2015, Bleichert et al., 2013)
        Orc4 - Orc3
        pull down, autoradiography, molecular weight estimation by staining, x-ray crystallography, anti bait coimmunoprecipitation, western blot, electron microscopy
        (Schmidt and Bleichert, 2020, Bleichert et al., 2018, Kopytova et al., 2016, Bleichert et al., 2015, Bleichert et al., 2013)
        Orc4 - Orc5
        x-ray crystallography, anti bait coimmunoprecipitation, western blot, cross-linking study, Identification by mass spectrometry, electron microscopy, pull down, molecular weight estimation by staining, autoradiography
        (Schmidt and Bleichert, 2020, Bleichert et al., 2018, Kopytova et al., 2016, Bleichert et al., 2015, Bleichert et al., 2013)
        Orc4 - Orc6
        pull down, molecular weight estimation by staining, fluorescence polarization spectroscopy, predetermined participant, electron microscopy, cross-linking study, Identification by mass spectrometry, autoradiography, x-ray crystallography, anti bait coimmunoprecipitation, western blot
        (Schmidt and Bleichert, 2020, Bleichert et al., 2018, Kopytova et al., 2016, Bleichert et al., 2015, Bleichert et al., 2013)
        Orc4 - PCID2
        anti tag coimmunoprecipitation, anti tag western blot
        (Kopytova et al., 2016)
        Orc4 - Su(var)205
        pull down, autoradiography
        (Pak et al., 1997)
        Orc4 - xmas
        anti tag coimmunoprecipitation, anti tag western blot, anti bait coimmunoprecipitation, western blot
        (Kopytova et al., 2016)
        Alleles Reported to Model Human Disease (Disease Ontology) (1 alleles)
        Orc4
        Models Based on Experimental Evidence ( 1 )
        Allele
        Disease
        Evidence
        References
        Orc4Y162C
        model of  Meier-Gorlin syndrome 2
        CEA
        (McDaniel et al., 2020)
        Modifiers Based on Experimental Evidence ( 0 )
        Allele
        Disease
        Interaction
        References
        Alleles Representing Disease-Implicated Variants
        Genetic Tools, Stocks and Reagents
        Sources of Stocks
        Contact lab of origin for a reagent not available from a public stock center.
        Bloomington Stock Center Disease Page
        Related mammalian, viral, bacterial, or synthetic transgenes
        Allele
        Transgene
        Publicly Available Stocks
        Selected Drosophila transgenes
        Allele
        Transgene
        Publicly Available Stocks
        RNAi constructs available
        Allele
        Transgene
        Publicly Available Stocks
        Orc4RNAi.UAS.cYa
        P{UAS-Orc4.RNAi.Y}
        w*; Bl1/CyO, P{Dfd-EYFP.wBmC}2; P{UAS-Orc4.RNAi.Y}3WBY/TM6B, Tb1
        Orc4GD4207
        P{GD4207}
        w1118; P{GD4207}v13613/CyO
        Orc4KK107650
        P{KK107650}
        P{KK107650}VIE-260B
        Orc4HMS00404
        P{TRiP.HMS00404}
        y1 sc* v1 sev21; P{TRiP.HMS00404}attP2
        Orc4NIG.2917R
        P{NIG.2917R}
        P{NIG.2917R}2
        Orc4GLC01628
        P{TRiP.GLC01628}
        y1 sc* v1 sev21; P{TRiP.GLC01628}attP40
        Selected Drosophila classical alleles
        Allele
        Allele class
        Mutagen
        Publicly Available Stocks
        Orc4Y162C
        CRISPR/Cas9
        Orc4null
        amorphic allele - genetic evidence
        CRISPR/Cas9
        References (5)