Construction of a high resolution linkage disequilibrium map to evaluate common genetic variation in<i>TP53</i>and neural tube defect risk in an Irish population

Pangilinan, Faith; Geiler, Kerry A; Dolle, Jessica; Troendle, James; Swanson, Deborah A.; Molloy, Anne M.; Sutton, Marie; Conley, Mary; Kirke, Peadar N.; Scott, John M.; Mills, James L.; Brody, Lawrence C.

doi:10.1002/ajmg.a.32504

Cited by 20 publications

(15 citation statements)

References 52 publications

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“…Snail2 and p53 play key roles during neural tube closure in many organisms, including humans (Pangilinan et al, 2008;Stegmann et al, 1999). Indeed, we observed a large number of neural tube defects (NTDs) in our experiments (data not shown), in agreement with a role for the p53-Snail2 regulatory loop in such defects.…”

Section: P53-snail2 Regulatory Loopsupporting

confidence: 82%

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

et al. 2011

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SUMMARYNeural crest development involves epithelial-mesenchymal transition (EMT), during which epithelial cells are converted into individual migratory cells. Notably, the same signaling pathways regulate EMT function during both development and tumor metastasis. p53 plays multiple roles in the prevention of tumor development; however, its precise roles during embryogenesis are less clear. We have investigated the role of p53 in early cranial neural crest (CNC) development in chick and mouse embryos. In the mouse, p53 knockout embryos displayed broad craniofacial defects in skeletal, neuronal and muscle tissues. In the chick, p53 is expressed in CNC progenitors and its expression decreases with their delamination from the neural tube. Stabilization of p53 protein using a pharmacological inhibitor of its negative regulator, MDM2, resulted in reduced SNAIL2 (SLUG) and ETS1 expression, fewer migrating CNC cells and in craniofacial defects. By contrast, electroporation of a dominant-negative p53 construct increased PAX7 + SOX9 + CNC progenitors and EMT/delamination of CNC from the neural tube, although the migration of these cells to the periphery was impaired. Investigating the underlying molecular mechanisms revealed that p53 coordinates CNC cell growth and EMT/delamination processes by affecting cell cycle gene expression and proliferation at discrete developmental stages; disruption of these processes can lead to craniofacial defects.

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Section: P53-snail2 Regulatory Loopsupporting

confidence: 82%

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

et al. 2011

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“…The strong linkage disequilibrium between Arg72Pro and polymorphisms PIN3 ( P < 0.0001), rs12947788 ( P = 0.0003), and rs12951053 ( P = 0.0003) confirms the findings of other studies [63, 64] and demonstrates that the modification serves as a marker of susceptibility and not as a consequence of mutational low doses of ionizing radiation.…”

Section: Discussionsupporting

confidence: 85%

Molecular Characterization ofTP53Gene in Human Populations Exposed to Low-Dose Ionizing Radiation

Costa

Alencar

Raiol-Moraes

et al. 2013

BioMed Research International

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Ionizing radiation, such as that emitted by uranium, may cause mutations and consequently lead to neoplasia in human cells. The TP53 gene acts to maintain genomic integrity and constitutes an important biomarker of susceptibility. The present study investigated the main alterations observed in exons 4, 5, 6, 7, and 8 of the TP53 gene and adjacent introns in Amazonian populations exposed to radioactivity. Samples were collected from 163 individuals. Occurrence of the following alterations was observed: (i) a missense exchange in exon 4 (Arg72Pro); (ii) 2 synonymous exchanges, 1 in exon 5 (His179His), and another in exon 6 (Arg213Arg); (iii) 4 intronic exchanges, 3 in intron 7 (C → T at position 13.436; C → T at position 13.491; T → G at position 13.511) and 1 in intron 8 (T → G at position 13.958). Alteration of codon 72 was found to be an important risk factor for cancer development (P = 0.024; OR = 6.48; CI: 1.29–32.64) when adjusted for age and smoking. Thus, TP53 gene may be an important biomarker for carcinogenesis susceptibility in human populations exposed to ionizing radiation.

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“…A large family-based study did not find risk associated with tested SNPs on TP35. However, another large case-control study of Irish patients with SB using 35 SNPs in the TP53 locus demonstrated two SNPs of the patient genotypes associated with risk and two SNPs in the maternal genotype conferring risk [Pangilinan et al, 2008]. Replication of risk association of TP53 in other samples should be performed to verify or refute these findings.…”

Section: Oxidative Stress/apoptosismentioning

confidence: 99%

Epidemiologic and genetic aspects of spina bifida and other neural tube defects

Au¹,

Ashley-Koch

Northrup³

2010

Dev Disabil Res Revs

308

233

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The worldwide incidence of neural tube defects (NTDs) ranges from 1.0 to 10.0 per 1,000 births with almost equal frequencies between two major categories: anencephaly and spina bifida (SB). Epidemiological studies have provided valuable insight for (a) researchers to identify nongenetic and genetic factors contributing to etiology, (b) public health officials to design and implement policies to prevent NTD pregnancies, and (c) individuals to take precautions to reduce the chance of having an NTD-affected pregnancy. Despite extensive research, our knowledge of the genetic etiology of human NTDs is limited. Although more than 200 small animal models with NTDs exist, most of these models do not replicate the human disease phenotype. Over a hundred candidate genes have been examined for risk association to human SB. The candidate genes studied include those important in folic acid metabolism, glucose metabolism, retinoid metabolism, and apoptosis. Many genes that regulate transcription in early embryogenesis and maintain planar cell polarity have also been tested as candidates. Additionally, genes identified through mouse models of NTDs have been explored as candidates. We do not know how many genes in the human genome may confer risk for NTDs in human. Less than 20% of the studied candidate genes have been determined to confer even a minor effect on risk association. Many studies have provided conflicting conclusions due to limitations in study design that potentially affect the power of statistical analysis. Future directions such as genomewide association studies (GWAS) and whole exome or even whole genome sequencing are discussed as possible avenues to identify genes that affect risk for human NTDs.

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Construction of a high resolution linkage disequilibrium map to evaluate common genetic variation inTP53and neural tube defect risk in an Irish population

Cited by 20 publications

References 52 publications

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

p53 coordinates cranial neural crest cell growth and epithelial-mesenchymal transition/delamination processes

Molecular Characterization ofTP53Gene in Human Populations Exposed to Low-Dose Ionizing Radiation

Epidemiologic and genetic aspects of spina bifida and other neural tube defects

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