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

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.

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Available from: Sarah Walker, Sep 27, 2015
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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.
    Metabolic Brain Disease 08/2015; DOI:10.1007/s11011-015-9712-y · 2.64 Impact Factor
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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.
    Biology Open 07/2015; 4(8). DOI:10.1242/bio.012914 · 2.42 Impact Factor
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    • "Modeling experiments in Xenopus egg extracts now bring these diverse threads together into a coherent reiteration of the fission yeast data by supporting the concept of waves of Cdk1/cyclin B feedback loop activities emanating from the centrosome (Chang and Ferrell 2013). A final twist to centrosomal control has been provided by the demonstration that pericentrin mutations alter the DNA damage checkpoint response (Griffith et al. 2008). This link had been anticipated by reports that centrosomal Chk1 played a critical role in determining the timing of mitotic commitment. "
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    ABSTRACT: The centrosome was discovered in the late 19th century when mitosis was first described. Long recognized as a key organelle of the spindle pole, its core component, the centriole, was realized more than 50 or so years later also to comprise the basal body of the cilium. Here, we chart the more recent acquisition of a molecular understanding of centrosome structure and function. The strategies for gaining such knowledge were quickly developed in the yeasts to decipher the structure and function of their distinctive spindle pole bodies. Only within the past decade have studies with model eukaryotes and cultured cells brought a similar degree of sophistication to our understanding of the centrosome duplication cycle and the multiple roles of this organelle and its component parts in cell division and signaling. Now as we begin to understand these functions in the context of development, the way is being opened up for studies of the roles of centrosomes in human disease. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.
    Cold Spring Harbor Perspectives in Medicine 02/2015; 7(1-2). DOI:10.1101/cshperspect.a015800 · 9.47 Impact Factor
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