Abstract
Large brain size is one of the defining characteristics of modern humans. Seckel syndrome (MIM 210600), a disorder of markedly reduced brain and body size, is associated with defective ATR-dependent DNA damage signaling. Only a single hypomorphic mutation of ATR has been identified in this genetically heterogeneous condition. We now report that mutations in the gene encoding pericentrin (PCNT)--resulting in the loss of pericentrin from the centrosome, where it has key functions anchoring both structural and regulatory proteins--also cause Seckel syndrome. Furthermore, we find that cells of individuals with Seckel syndrome due to mutations in PCNT (PCNT-Seckel) have defects in ATR-dependent checkpoint signaling, providing the first evidence linking a structural centrosomal protein with DNA damage signaling. These findings also suggest that other known microcephaly genes implicated in either DNA repair responses or centrosomal function may act in common developmental pathways determining human brain and body size.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Antigens / chemistry
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Antigens / genetics*
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Antigens / physiology
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Ataxia Telangiectasia Mutated Proteins
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Base Sequence
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Case-Control Studies
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Cell Cycle Proteins / genetics
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Cell Line
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Chromosomes, Human, Pair 22
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Codon
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Codon, Nonsense
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Consanguinity
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DNA Damage*
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Exons
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Frameshift Mutation
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Genes, Recessive
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Genetic Linkage
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Genome, Human
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Homozygote
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Humans
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Lod Score
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Lymphocytes / metabolism
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Microcephaly / genetics*
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Models, Biological
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Molecular Sequence Data
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Molecular Weight
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Mutagenesis, Insertional
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Mutation*
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Oligonucleotide Array Sequence Analysis
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Physical Chromosome Mapping
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Polymorphism, Single Nucleotide
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Protein Isoforms / chemistry
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Protein Isoforms / genetics
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Protein Serine-Threonine Kinases / genetics
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Protein Structure, Tertiary
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RNA Interference
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RNA, Small Interfering / metabolism
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Sequence Analysis, DNA
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Signal Transduction / genetics*
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Signal Transduction / physiology
Substances
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Antigens
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Cell Cycle Proteins
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Codon
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Codon, Nonsense
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Protein Isoforms
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RNA, Small Interfering
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pericentrin
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ATR protein, human
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Ataxia Telangiectasia Mutated Proteins
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Protein Serine-Threonine Kinases