Alternative titles; symbols
HGNC Approved Gene Symbol: ORC1
Cytogenetic location: 1p32.3 Genomic coordinates (GRCh38) : 1:52,372,829-52,409,503 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p32.3 | Meier-Gorlin syndrome 1 | 224690 | Autosomal recessive | 3 |
ORC1, a subunit of the origin recognition complex, is a key component of the DNA replication licensing machinery that also plays a role in controlling centriole and centrosome copy number in human cells independent of its role in DNA replication (Hemerly et al., 2009).
In the yeast Saccharomyces cerevisiae, DNA replication is initiated by the origin of replication complex (ORC), a 6-subunit protein. All 6 genes encoding this complex (ORC1 through ORC6) are essential for viability in yeast. Yeast ORC1 encodes the largest subunit of the ORC and contains a cell division cycle-nucleoside triphosphate binding domain that is conserved among several yeast transcriptional regulators. Gavin et al. (1995) used degenerate PCR to clone a human homolog of the yeast ORC1 gene. The human ORC1 gene encodes an 861-amino acid protein that is 27% identical to yeast Orc1. Gavin et al. (1995) showed that ORC1 and ORC2 (ORC2L; 601182) can be coimmunoprecipitated, suggesting that they form a complex in vivo.
By analysis of a somatic cell hybrid panel and by fluorescence in situ hybridization, Eki et al. (1996) mapped the ORC1L gene to 1p32.
Crystal Structure
Dueber et al. (2007) determined the 3.4-angstrom resolution structure of an archaeal Cdc6/Orc1 heterodimer bound to origin DNA. The structure demonstrated that, in addition to conventional DNA binding elements, initiators use their AAA+ ATPase domains to recognize origin DNA. Together these interactions establish the polarity of initiator assembly on the origin and induce substantial distortions into origin DNA strands. Biochemical and comparative analyses indicated that AAA+/DNA contacts observed in the structure are dynamic and evolutionarily conserved, suggesting that the complex forms a core component of the basal initiation machinery.
Gaudier et al. (2007) independently reported the structure of an archaeal origin recognition complex protein, ORC1, bound to an origin recognition box, a DNA sequence that is found in multiple copies at replication origins. The authors determined that DNA binding is mediated principally by a C-terminal winged helix domain that inserts deeply into the major and minor grooves, widening them both. However, additional DNA contacts are made with the N-terminal AAA+ domain, which inserts into the minor groove at a characteristic G-rich sequence, inducing a 35-degree bend in the duplex and providing directionality to the binding site. Both contact regions also induce substantial unwinding of the DNA.
Ohtani et al. (1996) showed that expression of human ORC1 is low in quiescent fibroblast cells and is induced by cell growth stimulation. They found that this control of expression is mediated by E2F (see 189971) transcriptional repression of the ORC1 promoter in quiescent cells. Activation of ORC1 transcription required G1 cyclin-dependent kinase activity. Ohtani et al. (1996) concluded that there is a direct link between the initiation of DNA replication and the cell growth regulatory pathway involving G1 cyclin-dependent kinase, the Rb tumor suppressor (614041), and E2F.
Mendez et al. (2002) found that the levels of ORC1 vary during the cell division cycle. In rapidly proliferating cells, ORC1 is expressed and targeted to chromatin as cells exit mitosis and prereplicative complexes are formed. Later, as cyclin A (123835) accumulates and cells enter S phase, ORC1 is ubiquitinated on chromatin and then degraded. ORC1 destruction occurs through the proteasome and is signaled in part by the SCF-SKP2 (see 601436) ubiquitin ligase complex. Other human ORC subunits are stable throughout the cell cycle. The regulation of ORC1 may be an important mechanism in maintaining the ploidy in human cells.
Hemerly et al. (2009) reported a role for the ORC1 protein in controlling centriole and centrosome copy number in human cells, independent of its role in DNA replication. Cyclin A (123835) promotes Orc1 localization to centrosomes, where Orc1 prevents cyclin E (123837)-dependent reduplication of both centrioles and centrosomes in a single cell division cycle. Hemerly et al. (2009) concluded that Orc1 is a regulator of centriole and centrosome reduplication as well as the initiation of DNA replication.
Bicknell et al. (2011) established a zebrafish morphant model using oligonucleotides targeting orc1 and observed substantially reduced embryo size at 5 days after fertilization, with 80% of injected embryos being structurally normal and viable with a general reduction in size of all tissues. The remaining embryos displayed a severe phenotype with abnormal body curvature and reduced viability, and the phenotype correlated with the degree of orc1 transcript depletion. Bicknell et al. (2011) observed that mcm5 (602696)-depleted zebrafish mutants had an identical phenotype to the viable 'dwarf' Orc1 zebrafish and exhibited similar levels of growth retardation; they suggested that the phenotype might be a direct consequence of impaired origin licensing rather than an indirect consequence of some other function of ORC1.
Kuo et al. (2012) showed that ORC1, a component of ORC (origin of replication complex), which mediates pre-DNA replication licensing, contains a bromo adjacent homology (BAH) domain that specifically recognizes histone H4 dimethylated at lysine-20 (H4K20me2, see 602822). Recognition of H4K20me2 is a property common to BAH domains present within diverse metazoan ORC1 proteins. Structural studies revealed that the specificity of the BAH domain for H4K20me2 is mediated by a dynamic aromatic dimethyl-lysine-binding cage and multiple intermolecular contacts involving the bound peptide. H4K20me2 is enriched at replication origins, and abrogating ORC1 recognition of H4K20me2 in cells impairs ORC1 occupancy at replication origins, ORC chromatin loading, and cell cycle progression. Mutation of the ORC1 BAH domain has been implicated in the etiology of Meier-Gorlin syndrome, a form of primordial dwarfism, and ORC1 depletion in zebrafish results in a Meier-Gorlin syndrome-like phenotype (Bicknell et al., 2011). Kuo et al. (2012) found that wildtype human ORC1, but not ORC1-H4K20me2-binding mutants, rescues the growth retardation of orc1 morphants. Moreover, zebrafish depleted of H4K20me2 have diminished body size, mirroring the phenotype of orc1 morphants. Kuo et al. (2012) concluded that their results identified the BAH domain as a novel methyl-lysine-binding module, thereby establishing the first direct link between histone methylation and the metazoan DNA replication machinery, and defining a pivotal etiologic role for the canonical H4K20me2 mark, via ORC1, in primordial dwarfism.
In 2 affected sibs from a consanguineous Saudi Arabian family with the Meier-Gorlin syndrome-1 form of microcephalic primordial dwarfism (MGORS1; 224690), Bicknell et al. (2011) identified homozygosity for a missense mutation in the candidate gene ORC1 (601902.0001). Screening of 204 additional individuals with similar microcephalic primordial dwarfism identified a further 3 families with biallelic missense mutations in ORC1 (601902.0002-601902.0004). All of the mutations involved conserved residues, and functional analyses revealed that the mutations disrupted pre-replicative complex formation and origin activation and perturbed S-phase entry and progression.
In a follow-up study, Bicknell et al. (2011) analyzed the ORC1 gene in 2 brothers with a complex lethal developmental syndrome involving profound growth retardation and microcephaly and identified compound heterozygosity for a missense (R105Q; 601902.0003) and a frameshift mutation (601902.0005). Subsequent sequencing of ORC1 in 33 individuals with an established diagnosis of Meier-Gorlin syndrome revealed 2 probands who were compound heterozygous for R105Q and a splice site mutation (601902.0006) in the ORC1 gene, 1 of whom was the patient originally described by Gorlin et al. (1975).
In a woman with Meier-Gorlin syndrome who was negative for mutations in the ORC4 gene, Guernsey et al. (2011) sequenced candidate genes encoding ORC complex or pathway-associated proteins and identified compound heterozygosity for missense mutations in the ORC1 gene (601902.0003 and 601902.0007).
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human ORC1 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a brother and sister from a consanguineous Saudi Arabian family with the Meier-Gorlin syndrome-1 form of microcephalic primordial dwarfism (MGORS1; 224690), Bicknell et al. (2011) identified homozygosity for a 380A-G transition in exon 4 of the ORC1 gene, resulting in a glu127-to-gly (E127G) substitution at a conserved residue in the BAH domain. The mutation segregated appropriately for an autosomal recessive disorder in the family and was not found in 380 controls. The 4.5-year-old brother had a small chin, mildly small ears, and full lips; his 8-month-old sister had a small anterior fontanel and relatively small ears. Analysis of lymphoblastoid cells from 1 of the affected sibs showed substantially reduced levels of ORC1 compared to control cells, and parental cell lines had partially reduced ORC1. Patient cells also progressed more slowly through S-phase than control cells, and markedly less labeled DNA from patient cells moved to a higher molecular weight compared to those of controls over a 60-minute growth period. Bicknell et al. (2011) concluded that ORC1 deficiency delays S-phase entry, thereby prolonging the G1 phase.
In a 4.5-year-old girl with the Meier-Gorlin syndrome-1 form of microcephalic primordial dwarfism (MGORS1; 224690), from a consanguineous family of Syrian origin, Bicknell et al. (2011) identified homozygosity for a 266T-C transition in exon 4 of the ORC1 gene, resulting in a phe89-to-ser (F89S) substitution at a conserved residue in the BAH domain. The mutation segregated appropriately for an autosomal recessive disorder in the family and was not found in 380 controls. The patient had hyperextended and dislocated knees at birth; the posteriorly dislocated tibia was surgically corrected. Patellae were present bilaterally. She also underwent surgery for craniosynostosis. Facial dysmorphism included mild micrognathia, small ears, mild synophrys, and full lips. Intellect was normal.
In a 13-year-old boy with the Meier-Gorlin syndrome-1 form of microcephalic primordial dwarfism (MGORS1; 224690), Bicknell et al. (2011) identified homozygosity for a 314G-A transition in exon 4 of the ORC1 gene, resulting in an arg105-to-gln (R105Q) substitution at a conserved residue in the BAH domain. The boy had moderate learning difficulty, relatively large ears, short philtrum, and full lips. He had undergone pulmonary lobectomy for lobar emphysema, and had left hemiplegia as a consequence of intraventricular hemorrhage associated with severe prematurity. Skeletal survey showed slender long bones, cupped distal metaphyses of metacarpals, short fourth metacarpal, and patellae were present.
In an unrelated 7-year-old girl with MGORS1, Bicknell et al. (2011) identified compound heterozygosity for R105Q and a 2159G-A transition in exon 15 of the ORC1 gene, resulting in an arg720-to-gln (R720Q; 601902.0004) substitution at a conserved residue between the AAA and WH domains. She had normal intellect, normally shaped ears with small lobules and narrow auricular canals, severe conductive hearing loss and a high-pitched voice, slightly prominent nose, bifid uvula, and full lips. Skeletal survey showed mildly gracile long bones, minimal metaphyseal widening, some undertubulation in the midshaft of some long bones, and delayed bone age; patellae were present. Functional studies using her fibroblasts suggested that the mutant ORC1 failed to initiate replication and slowed the rate of S-phase progression.
In 2 brothers with a complex lethal developmental syndrome involving profound growth retardation and microcephaly, Bicknell et al. (2011) identified compound heterozygosity for the R105Q mutation and a 2-bp deletion/1-bp insertion (2000delGTinsA; 601902.0005) in exon 13 of the ORC1 gene, causing a frameshift predicted to result in premature termination. The proband had an extensive number of developmental malformations including severe cortical dysplasia, congenital emphysema, absence of the pancreatic tail and retroflexion of the knees, as well as micropenis, blepharophimosis, and cranial suture stenosis. Bicknell et al. (2011) suggested that the more severe phenotype was the result of greater loss of function.
In 2 patients with an established diagnosis of MGORS1, 1 of whom was the male patient originally described by Gorlin et al. (1975) and the other an English girl previously reported by Bongers et al. (2001), Bicknell et al. (2011) identified compound heterozygosity for R105Q and a 1482-2A-G transition at the splice acceptor site in intron 9 of the ORC1 gene (601902.0006). Bicknell et al. (2011) noted that the R105Q mutation was inherited by the male patient on a haplotype shared by the deceased brothers, consistent with common ancestry; however, the R105Q mutation in the girl and the 2 splice acceptor site mutations appeared to have arisen independently. None of these mutations was found in 380 control chromosomes.
In a woman with Meier-Gorlin syndrome who was previously reported by Shalev and Hall (2003), Guernsey et al. (2011) identified compound heterozygosity for the R105Q mutation and an arg666-to-trp (R666W; 601902.0007) substitution in the conserved ATPase domain of ORC1. Her mother was heterozygous for 1 of the variants; DNA was unavailable from her father.
For discussion of the arg720-to-gln (R720Q) mutation in the ORC1 gene that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome (MGORS1; 224690) by Bicknell et al. (2011), see 601902.0003.
For discussion of the 2-bp deletion/1-bp insertion (2000delGTinsA) in the ORC1 gene that was found in compound heterozygous state in 2 sibs with Meier-Gorlin syndrome (MGORS1; 224690) by Bicknell et al. (2011), see 601902.0003.
For discussion of the splice site mutation in the ORC1 gene that was found in compound heterozygous state in patients with Meier-Gorlin syndrome (MGORS1; 224690) by Bicknell et al. (2011), see 601902.0003.
For discussion of the arg666-to-trp (R666W) mutation in the ORC1 gene that was found in compound heterozygous state in a patient with Meier-Gorlin syndrome (MGORS1; 224690) by Guernsey et al. (2011), see 601902.0003.
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Kuo, A. J., Song, J., Cheung, P., Ishibe-Murakami, S., Yamazoe, S., Chen, J. K., Patel, D. J., Gozani, O. The BAH domain of ORC1 links H4K20me2 to DNA replication licensing and Meier-Gorlin syndrome. Nature 484: 115-119, 2012. [PubMed: 22398447] [Full Text: https://doi.org/10.1038/nature10956]
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