title: Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome.
abstract: Studies into disorders of extreme growth failure (for example, Seckel syndrome and Majewski osteodysplastic primordial dwarfism type II) have implicated fundamental cellular processes of DNA damage response signaling and centrosome function in the regulation of human growth. Here we report that mutations in ORC1, encoding a subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome. We establish that these mutations disrupt known ORC1 functions including pre-replicative complex formation and origin activation. ORC1 deficiency perturbs S-phase entry and S-phase progression. Additionally, we show that Orc1 depletion in zebrafish is sufficient to markedly reduce body size during rapid embryonic growth. Our data suggest a model in which ORC1 mutations impair replication licensing, slowing cell cycle progression and consequently impeding growth during development, particularly at times of rapid proliferation. These findings establish a novel mechanism for the pathogenesis of microcephalic dwarfism and show a surprising but important developmental impact of impaired origin licensing.
authors.affiliation: Medical Research Council (MRC) Human Genetics Unit (HGU), Institute for Genetics and Molecular Medicine, Western General Hospital, Edinburgh, UK.
authors.forename: Louise S
authors.initials: LS
authors.lastname: Bicknell
authors.forename: Sarah
authors.initials: S
authors.lastname: Walker
authors.forename: Anna
authors.initials: A
authors.lastname: Klingseisen
authors.forename: Tom
authors.initials: T
authors.lastname: Stiff
authors.forename: Andrea
authors.initials: A
authors.lastname: Leitch
authors.forename: Claudia
authors.initials: C
authors.lastname: Kerzendorfer
authors.forename: Carol-Anne
authors.initials: CA
authors.lastname: Martin
authors.forename: Patricia
authors.initials: P
authors.lastname: Yeyati
authors.forename: Nouriya
authors.initials: N
authors.lastname: Al Sanna
authors.forename: Michael
authors.initials: M
authors.lastname: Bober
authors.forename: Diana
authors.initials: D
authors.lastname: Johnson
authors.forename: Carol
authors.initials: C
authors.lastname: Wise
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Jackson
authors.forename: Mark
authors.initials: M
authors.lastname: O'Driscoll
authors.forename: Penny A
authors.initials: PA
authors.lastname: Jeggo
mesh_terms: D000293:Adolescent; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D065817:Congenital Microtia; D003241:Consanguinity; D004247:DNA / Q000235:genetics; D004392:Dwarfism / Q000235:genetics*; D004423:Ear / Q000002:abnormalities; D005260:Female; D055106:Genome-Wide Association Study; D006130:Growth Disorders / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000235:genetics*; D008844:Micrognathism / Q000235:genetics; D008957:Models, Genetic; D008958:Models, Molecular; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000737:chemistry / Q000235:genetics; D020125:Mutation, Missense; D051738:Origin Recognition Complex / Q000737:chemistry / Q000172:deficiency / Q000235:genetics*; D010329:Patella / Q000002:abnormalities; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017434:Protein Structure, Tertiary; D016196:S Phase / Q000235:genetics; D012529:Saudi Arabia; D017386:Sequence Homology, Amino Acid; D015027:Zebrafish / Q000196:embryology / Q000235:genetics; D029961:Zebrafish Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D050505:Mutant Proteins; C497223:ORC1 protein, human; D051738:Origin Recognition Complex; D029961:Zebrafish Proteins; D004247:DNA