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Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome
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Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome
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Journal Article
Mutations in ORC1, encoding the largest subunit of the origin recognition complex, cause microcephalic primordial dwarfism resembling Meier-Gorlin syndrome
2011
Overview
Mark O'Driscoll, Andrew Jackson and colleagues report the identification of mutations in
ORC1
in individuals with microcephalic primordial dwarfism.
ORC1
encodes the largest subunit of the origin recognition complex.
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.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Animal Genetics and Genomics
/ Animals
/ Biological and medical sciences
/ Biomedical and Life Sciences
/ Cancer
/ Child
/ Dwarfism
/ Female
/ Fundamental and applied biological sciences. Psychology
/ Genetics
/ Genetics of eukaryotes. Biological and molecular evolution
/ Genome-Wide Association Study
/ Humans
/ Infant
/ letter
/ Male
/ Mutation
/ Origin Recognition Complex - chemistry
/ Origin Recognition Complex - deficiency
/ Origin Recognition Complex - genetics
/ Pedigree
/ Polymorphism, Single Nucleotide
/ Proteins
/ Sequence Homology, Amino Acid
/ Single nucleotide polymorphisms
/ Tumors of the skin and soft tissue. Premalignant lesions
