Griffith, E. et al. Mutations in pericentrin cause Seckel syndrome with defective ATR-dependent DNA damage signaling. Nature Genet. 40, 232-236

Medical Research Council (MRC) Human Genetics Unit, Western General Hospital, Crewe Road, Edinburgh EH4 2XU, UK.
Nature Genetics (Impact Factor: 29.35). 03/2008; 40(2):232-6. DOI: 10.1038/ng.2007.80
Source: PubMed


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.

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    • "In addition to chromosomal missegregation, altered centriole biogenesis is associated with human developmental growth disorders, such as primordial dwarfism and MCPH (Mochida and Walsh, 2001, 2004; Woods et al., 2005; Griffith et al., 2008; Rauch et al., 2008; Thornton and Woods, 2009). "
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    ABSTRACT: eLife digest When a cell divides, the chromosomes that contain the genetic blueprint for the cell must be replicated and shared between the two new cells. A structure called the centrosome organizes the cellular machinery that separates the chromosome copies during cell division. At the center of each centrosome are two cylindrical microtubule-based structures called centrioles. Mutations in certain proteins that interact with the centrosome cause a neurodevelopmental disorder called primary microcephaly. People born with microcephaly have unusually small heads and brains. As a result, they may have difficulties with mental tasks. Scientists do not know exactly how these ‘microcephaly-associated’ proteins normally interact with the centrosomes or what they do at the centrosomes, so it is difficult to work out what goes wrong in people with microcephaly. One idea is that the proteins help to duplicate the centrioles before a cell divides. If this duplication does not occur, a cell cannot divide properly; so, people with mutations that interfere with centriole duplication cannot grow enough brain cells. Now, Kodani et al. have examined how these microcephaly-associated proteins work with ‘satellite’ proteins that congregate near the centrosome to duplicate centrioles. The satellite proteins help to recruit four microcephaly-associated proteins to the centrosome, where they are built into a ring. The microcephaly-associated proteins congregate at the centrosome in a particular order, with each protein recruiting the next one in the sequence. Once all four are in place near the centrosome, an enzyme that helps to duplicate the centrioles joins them. Further experiments suggest that mutations that affect one of the satellite proteins—known as CEP90—may cause microcephaly. Future analysis of how microcephaly-associated genes work may reveal the cell biological mechanisms by which centrioles participate in brain development. DOI:
    Full-text · Article · Aug 2015 · eLife Sciences
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    • "The MOPD II disease is associated with defects in the pericentrin (PCNT) gene, which encodes a centrosomal protein functioning in the organization of mitotic spindles. To date, numerous mutations in this gene have been reported to cause primordial dwarfism and other disorders such as Seckel syndrome (Griffith et al. 2008; Rauch et al. 2008; Willems et al. 2010; Unal et al. 2014). Although dwarfism has been reported to be partly due to the loss of microtubule integrity function of pericentrin (Delaval and Doxsey 2010; Sam et al. 2015), the genomic basis behind most clinical features of MOPD II remains unclear. "
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    ABSTRACT: Microcephalic osteodysplastic primordial dwarfism type II (MOPD II) is a highly detrimental human autosomal inherited recessive disorder. The hallmark characteristics of this disease are intrauterine and postnatal growth restrictions, with some patients also having cerebrovascular problems such as cerebral aneurysms. The genomic basis behind most clinical features of MOPD II remains largely unclear. The aim of this work was to identify the genetic defects in a Chinese family with MOPD II associated with multiple intracranial aneurysms. The patient had typical MOPD II syndrome, with subarachnoid hemorrhage and multiple intracranial aneurysms. We identified three novel mutations in the PCNT gene, including one single base alteration (9842A>C in exon 45) and two deletions (Del-C in exon 30 and Del-16 in exon 41). The deletions were co-segregated with the affected individual in the family and were not present in the control population. Computer modeling demonstrated that the deletions may cause drastic changes on the secondary and tertiary structures, affecting the hydrophilicity and hydrophobicity of the mutant proteins. In conclusion, we identified two novel mutations in the PCNT gene associated with MOPD II and intracranial aneurysms, and the mutations were expected to alter the stability and functioning of the protein by computer modeling.
    Full-text · Article · Aug 2015 · Metabolic Brain Disease
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    • "Interestingly, several studies in vertebrate cells have suggested a link between Pericentrin and Cdk5Rap2/Cep215 function in PCM recruitment (Buchman et al., 2010; Chen et al., 2014; Haren et al., 2009; Kim and Rhee, 2014) and also in maintaining centriole cohesion and regulating centriole disengagement (Barrera et al., 2010; Lee and Rhee, 2012; Pagan et al., 2015). Moreover, mutations in Cdk5Rap2 have been linked to autosomal primary microcephaly (MCPH) while mutations in Pericentrin have been linked to microcephalic osteodysplastic primordial dwarfism (Bond et al., 2005; Griffith et al., 2008; Rauch et al., 2008). "
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    ABSTRACT: Centrosomes comprise a pair of centrioles surrounded by a matrix of pericentriolar material (PCM). In vertebrate cells, Pericentrin plays an important part in mitotic PCM assembly, but the Drosophila Pericentrin-like protein (PLP) appears to have a more minor role in mitotic fly cells. Here we investigate the function of PLP during the rapid mitotic cycles of the early Drosophila embryo. Unexpectedly, we find that PLP is specifically enriched in the outer-most regions of the PCM, where it largely co-localizes with the PCM scaffold protein Cnn. In the absence of PLP the outer PCM appears to be structurally weakened, and it rapidly disperses along the centrosomal MTs. As a result, centrosomal MTs are subtly disorganized in embryos lacking PLP, although mitosis is largely unperturbed and these embryos develop and hatch at near-normal rates. Y2H analysis reveals that PLP can potentially form multiple interactions with itself and with the PCM recruiting proteins Asl, Spd-2 and Cnn. A deletion analysis suggests that PLP participates in a complex network of interactions that ultimately help to strengthen the PCM. © 2015. Published by The Company of Biologists Ltd.
    Full-text · Article · Jul 2015 · Biology Open
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