The ORC1 gene encodes a protein that is important in DNA replication. This protein belongs to a group known as the origin recognition complex (ORC). ORC binds to certain regions of DNA known as origins of replication where the process of DNA copying begins. This complex attracts additional proteins to bind to it, forming a larger group of proteins called the pre-replication complex. Replication is then able to begin at that location. This tightly controlled process, called replication licensing, helps ensure that DNA replication occurs only once per cell division and is required for cells to divide. The ORC1 protein is also involved in the copying of centrosomes and centrioles, which are important for the process of cell division. ORC1 blocks centrosomes and centrioles from being copied more than once, which is key to normal cell division.
Defects in the ORC1 gene are known to cause Meier-Gorlin syndrome.
The ORC1 gene is located on the long (q) arm of chromosome 1 at position 32. It spans over 31,643 bases and contains 18 exons. The ORC1 protein consists of 861 amino acids, and has both an AAA+ and a winged-helix motif. The AAA+ motif is characteristic of ATP-dependent clamp-loading proteins. The levels of ORC1 vary along with the stage of the cell cycle the cell is in. To date, different mutations that cause Meier-Gorlin syndrome have been identified in this gene. Some of these are missense and others are frameshift mutations.
Bicknell et al. (2011) studied a cohort of nine members of a consanguineous Saudi-Arabian family with two children who had microcephalic primordial dwarfism. He identified a single large homozygous region on chromosome 1p32 which was refined by microsatellite genotyping to a 15.6-cM region containing 105 annotated genes. ORC1 gene was evaluated as a candidate gene, in part because the encoded protein, ORC1, regulates centrosome duplication. Sequencing the 16 coding exons of ORC1 in the affected siblings revealed a homozygous A>G transition (c.314A>G) in exon 4 generating a non-conservative amino acid substitution (p.Glu127Gly). Screening of 204 additional individuals with microcephalic primordial dwarfism identified another Syrian family with a c.266T>C (p.Phe89Ser) missense mutation in the same gene. Both mutations segregated appropriately in the families for an autosomal recessive disorder and were not present in 380 controls.
See Saudi Arabia > Bicknell et al., 2011