title: Mutations in origin recognition complex gene ORC4 cause Meier-Gorlin syndrome.
abstract: Meier-Gorlin syndrome is a rare autosomal recessive genetic condition whose primary clinical hallmarks include small stature, small external ears and small or absent patellae. Using marker-assisted mapping in multiple families from a founder population and traditional coding exon sequencing of positional candidate genes, we identified three different mutations in the gene encoding ORC4, a component of the eukaryotic origin recognition complex, in five individuals with Meier-Gorlin syndrome. In two such individuals that were negative for mutations in ORC4, we found potential mutations in ORC1 and CDT1, two other genes involved in origin recognition. ORC4 is well conserved in eukaryotes, and the yeast equivalent of the human ORC4 missense mutation was shown to be pathogenic in functional assays of cell growth. This is the first report, to our knowledge, of a germline mutation in any gene of the origin recognition complex in a vertebrate organism.
authors.affiliation: Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada.
authors.forename: Duane L
authors.initials: DL
authors.lastname: Guernsey
authors.forename: Makoto
authors.initials: M
authors.lastname: Matsuoka
authors.forename: Haiyan
authors.initials: H
authors.lastname: Jiang
authors.forename: Susan
authors.initials: S
authors.lastname: Evans
authors.forename: Christine
authors.initials: C
authors.lastname: Macgillivray
authors.forename: Mathew
authors.initials: M
authors.lastname: Nightingale
authors.forename: Scott
authors.initials: S
authors.lastname: Perry
authors.forename: Meghan
authors.initials: M
authors.lastname: Ferguson
authors.forename: Marissa
authors.initials: M
authors.lastname: LeBlanc
authors.forename: Jean
authors.initials: J
authors.lastname: Paquette
authors.forename: Lysanne
authors.initials: L
authors.lastname: Patry
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Rideout
authors.forename: Aidan
authors.initials: A
authors.lastname: Thomas
authors.forename: Andrew
authors.initials: A
authors.lastname: Orr
authors.forename: Chris R
authors.initials: CR
authors.lastname: McMaster
authors.forename: Jacques L
authors.initials: JL
authors.lastname: Michaud
authors.forename: Cheri
authors.initials: C
authors.lastname: Deal
authors.forename: Sylvie
authors.initials: S
authors.lastname: Langlois
authors.forename: Duane W
authors.initials: DW
authors.lastname: Superneau
authors.forename: Sandhya
authors.initials: S
authors.lastname: Parkash
authors.forename: Mark
authors.initials: M
authors.lastname: Ludman
authors.forename: David L
authors.initials: DL
authors.lastname: Skidmore
authors.forename: Mark E
authors.initials: ME
authors.lastname: Samuels
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D065817:Congenital Microtia; D003241:Consanguinity; D017124:Conserved Sequence; D004247:DNA / Q000235:genetics; D004423:Ear / Q000002:abnormalities / Q000473:pathology; D005260:Female; D018703:Founder Effect; D006130:Growth Disorders / Q000235:genetics / Q000473:pathology; D006239:Haplotypes; D006801:Humans; D008297:Male; D008844:Micrognathism / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D051738:Origin Recognition Complex / Q000235:genetics*; D010329:Patella / Q000002:abnormalities / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017386:Sequence Homology, Amino Acid
chemical_list: C467199:CDT1 protein, human; D018797:Cell Cycle Proteins; C497223:ORC1 protein, human; C109152:ORC4 protein, human; D051738:Origin Recognition Complex; D004247:DNA