Alternative titles; symbols
HGNC Approved Gene Symbol: ORC6
Cytogenetic location: 16q11.2 Genomic coordinates (GRCh38) : 16:46,689,659-46,698,394 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q11.2 | Meier-Gorlin syndrome 3 | 613803 | Autosomal recessive | 3 |
The origin recognition complex (ORC) comprises a highly conserved set of proteins which are bound to origins of DNA replication and mediate the initiation of DNA replication. The ORC6 gene encodes the smallest subunit of human ORC. During mitosis, ORC6 localizes to kinetochores and to a reticular-like structure around the cell periphery. It has been implicated in coordinating chromosome replication and segregation with cytokinesis (Prasanth et al., 2002).
Dhar and Dutta (2000) cloned the human ORC6 gene. The 252-amino acid human ORC6L protein is 28% identical to ORC6 protein from Drosophila.
Dhar and Dutta (2000) determined that the ORC6 gene contains 7 exons spanning 9 kb
By identification of homologous sequence within a BAC clone (GenBank AC007225), Dhar and Dutta (2000) mapped the ORC6 gene to chromosome 16q12.
Dhar and Dutta (2000) observed that human ORC6 protein interacted with several other cellular proteins, it did not physically interact with other ORC subunits.
Prasanth et al. (2002) found that during mitosis human ORC6 localizes to kinetochores and to a reticular-like structure around the cell periphery. As chromosomes segregate during anaphase, the reticular structures align along the plane of cell division and some ORC6 localizes to the midbody before cells separate. Silencing of ORC6 expression by small interfering RNA (siRNA) resulted in cells with multipolar spindles, aberrant mitosis, formation of multinucleated cells, and decreased DNA replication. Prolonged periods of ORC6 depletion caused a decrease in cell proliferation and increased cell death. Prasanth et al. (2002) concluded that their results implicate ORC6 as an essential gene that coordinates chromosome replication and segregation with cytokinesis.
In 3 sibs with the Meier-Gorlin syndrome-3 form of microcephalic primordial dwarfism (MGORS3; 613803), Bicknell et al. (2011) identified compound heterozygosity for a nonsense and a missense mutation in the ORC6 gene (607213.0001 and 607213.0002, respectively).
De Munnik et al. (2012) reported 4 patients with Meier-Gorlin syndrome who were compound heterozygous for a missense and a splice site mutation in the ORC6 gene (607213.0003-607213.0004).
In 2 affected fetuses from an Ashkenazi Jewish family, Shalev et al. (2015) identified homozygosity for a 4-bp deletion in the ORC6 gene (607213.0005) for which the unaffected first-cousin parents and 2 healthy sisters were heterozygous. The authors noted that homozygosity for a null mutation in ORC6 caused severely abnormal embryologic development, suggesting a genotype-phenotype correlation.
In a sister and 2 brothers with Meier-Gorlin syndrome-3 (MGORS3; 613803) from a consanguineous Turkish Kurd family previously reported by Lacombe et al. (1994), Bicknell et al. (2011) identified compound heterozygosity for a 2-bp deletion (257_258delTT) in exon 3 of the ORC6 gene, predicted to cause a frameshift and premature termination of the protein, and a 695A-C transversion in exon 7, resulting in a tyr232-to-ser (Y232S; 607213.0002) substitution at a highly conserved residue in the C terminus. Neither mutation was found in 380 control chromosomes.
For discussion of the tyr232-to-ser (Y232S) mutation in the ORC6 gene that was found in compound heterozygous state in patients with Meier-Gorlin syndrome-3 (MGORS3; 613803) by Bicknell et al. (2011), see 607213.0001.
In 4 patients with Meier-Gorlin syndrome-3 (MGORS3; 613803), de Munnik et al. (2012) identified compound heterozygosity for 2 mutations in the ORC6 gene: a c.2T-C transition within the initial met of the transcription start site (MET1?), and a splice site mutation (c.449+5G-A; 607213.0004).
For discussion of the c.449+5G-A transition in the ORC6 gene that was found in compound heterozygous state in patients with Meier-Gorlin syndrome-3 (MGORS3; 613803) by de Munnik et al. (2012), see 607213.0003.
In 2 fetuses from an Ashkenazi Jewish family with Meier-Gorlin syndrome-3 (MGORS3; 613803), originally described by Shalev (2007), Shalev et al. (2015) identified homozygosity for a 4-bp deletion (chr16.46,729,968delAGAA, GRCh37) (c.602_605delAGAA) in the ORC6 gene, causing a frameshift predicted to result in a premature termination codon (Lys202ArgfsTer1). The deletion was present in heterozygosity in the unaffected first-cousin parents and 2 healthy sisters, and was not found in the ExAC database.
Bicknell, L. S., Bongers, E. M. H. F., Leitch, A., Brown, S., Schoots, J., Harley, M. E., Aftimos, S., Al-Aama, J. Y., Bober, M., Brown, P. A. J., van Bokhoven, H., Dean, J., and 15 others. Mutations in the pre-replication complex cause Meier-Gorlin syndrome. Nature Genet. 43: 356-359, 2011. [PubMed: 21358632] [Full Text: https://doi.org/10.1038/ng.775]
de Munnik, S. A., Bicknell, L. S., Aftimos, S., Al-Aama, J. Y., van Bever, Y., Bober, M. B., Clayton-Smith, J., Edrees, A. Y., Feingold, M., Fryer, A., van Hagen, J. M., Hennekam, R. C., and 22 others. Meier-Gorlin syndrome genotype-phenotype studies: 35 individuals with pre-replication complex gene mutations and 10 without molecular diagnosis. Europ. J. Hum. Genet. 20: 598-606, 2012. [PubMed: 22333897] [Full Text: https://doi.org/10.1038/ejhg.2011.269]
Dhar, S. K., Dutta, A. Identification and characterization of the human ORC6 homolog. J. Biol. Chem. 275: 34983-34988, 2000. [PubMed: 10945994] [Full Text: https://doi.org/10.1074/jbc.M006069200]
Lacombe, D., Toutain, A., Gorlin, R. J., Oley, C. A., Battin, J. Clinical identification of a human equivalent to the short ear (se) murine phenotype. Ann. Genet. 37: 184-191, 1994. [PubMed: 7710253]
Prasanth, S. G., Prasanth, K. V., Stillman, B. Orc6 involved in DNA replication, chromosome segregation, and cytokinesis. Science 297: 1026-1031, 2002. [PubMed: 12169736] [Full Text: https://doi.org/10.1126/science.1072802]
Shalev, S. A., Khayat, M., Etty, D.-S., Elpeleg, O. Further insight into the phenotype associated with a mutation in the ORC6 gene, causing Meier-Gorlin syndrome 3. Am. J. Med. Genet. 167A: 607-611, 2015. [PubMed: 25691413] [Full Text: https://doi.org/10.1002/ajmg.a.36906]
Shalev, S. A. A syndrome characterized by intra-uterine lower limb dislocation, gracile bones, clubfeet, and other skeletal features. (Letter) Am. J. Med. Genet. 143A: 395-398, 2007. [PubMed: 17256795] [Full Text: https://doi.org/10.1002/ajmg.a.31580]