The human T locus and spina bifida risk

Jensen, Liselotte E.; Barbaux, Sandrine; Hoess, Katy; Fraterman, Sven; Whitehead, Alexander S.; Mitchell, Laura E.

doi:10.1007/s00439-004-1185-8

Cited by 27 publications

(21 citation statements)

References 62 publications

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“…46,47 In contrast, heterozygous brachyury loss in mice results in a short tail and notochordal abnormalities, and in humans, congenital vertebral malformations (hemi vertebra, vertebral bars, supernumerary vertebrae, butterfly and wedge shaped vertebrae), neural tube defects (spina bifida and anencephaly) and sacral agenesis are associated with genetic variations in brachyury, the functions of which are variable and not always clear. [48][49][50] The failure to detect mutations in any of the coding regions, splice junctions and promoter region of this gene in 23 chordomas and the failure to show amplification of brachyury in 36 of 39 chordomas imply that the expression of brachyury mRNA and protein is likely to be driven by events in upstream molecules. Furthermore, despite the minor allelic gain of brachyury in three cases, a finding which corresponds to the array comparative genomic hybridisation data published earlier, we consider that amplification of this gene is also unlikely to account for the driving force in the growth and development of this tumour in view of the low copy number of the gene in the small number of cases that was identified.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

et al. 2009

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Chordomas are rare primary malignant bone tumours that derive from notochord precursor cells and express brachyury, a molecule involved in notochord development. Little is known about the genetic events responsible for driving the growth of this tumour, but it is well established that brachyury is regulated through fibroblastic growth factor receptors (FGFRs) through RAS/RAF/MEK/ERK and ETS2 in ascidian, Xenopus and zebrafish, although little is known about its regulation in mammals. The aim of this study was to attempt to identify the molecular genetic events that are responsible for the pathogenesis of chordomas with particular focus on the FGFR signalling pathway on the basis of the evidence in the ascidian and Xenopus models that the expression of brachyury requires the activation of this pathway. Immunohistochemistry showed that 47 of 50 chordomas (94%) expressed at least one of the FGFRs, and western blotting showed phosphorylation of fibroblast growth factor receptor substrate 2 alpha (FRS2a), an adaptor signalling protein, that links FGFR to the RAS/RAF/MEK/ ERK pathway. Screening for mutations in brachyury (all coding exons and promoter), FGFRs 1-4 (previously reported mutations), KRAS (codons 12, 13, 51, 61) and BRAF (exons 11 and 15) failed to show any genetic alterations in 23 chordomas. Fluorescent in situ hybridisation analysis on FGFR4, ETS2 and brachyury failed to show either amplification of these genes, although there was minor allelic gain in brachyury in three tumours, or translocation for ERG and ETS2 loci. The key genetic events responsible for the initiation and progression of chordomas remain to be discovered.

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Section: Discussionmentioning

confidence: 99%

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

et al. 2009

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“…Other gene pathways, such as those genes that affect metabolism in diabetes and obesity, those affected by known teratogenic agents, those active in embryonic development, and those involved in DNA repair are also being investigated. 18,20,22,37,41 Open spinal dysraphisms are associated with trisomies 13 and 18, and have been reported with trisomies 2, 9, 14, 15, 16, 20, and 21. Neural tube defects have also been associated with partial trisomy of individual chromosomes.…”

Section: Folic Acidmentioning

confidence: 94%

“…Meckel syndrome, Waardenburg syndrome, and genetic abnormalities associated with 13q deletion syndrome. 1,11,18,[20][21][22]41,42 PRENATAL TESTING AND DIAGNOSTIC IMAGING E levated serum ␣-fetoprotein (AFP) testing during pregnancy helps identify the presence of open spinal defects. The optimum time for screening is 16 weeks.…”

Section: Folic Acidmentioning

confidence: 99%

Part 2

Mc¹

2006

Advances in Neonatal Care

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Spinal dysraphism includes a constellation of frequent and potentially complex malformations of the spine and spinal cord. Open spinal dysraphisms, the majority of which are myelomeningoceles, have a number of associated morbidities that require both immediate and lifelong medical care. The role of the neonatal nurse includes the immediate stabilization of the affected infant, systematic examination of the malformation, and implementation of evidence-based protocols to ameliorate the associated medical problems. Coordination of care and communication and support of the family are essential aspects of care. This article reviews the embryology of open spinal dysraphisms and the steps needed to stabilize and evaluate affected infants.

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“…They observed a bias in transmission of the C allele from heterozygous parents to offspring with neural tube defects in Dutch and UK families. Jensen et al [25] found that heterozygous parents transmitted the C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance. Moreover, the analyses suggested that the C allele acts in a dominant fashion, such that individuals carrying 1 or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with 0 copies.…”

Section: Relationship Of the T Gene To Human Diseasesmentioning

confidence: 97%

Identification of a Novel Mouse Brachyury (T) Allele Causing a Short Tail Mutation in Mice

Shao

Chen

et al. 2010

Cell Biochem Biophys

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Mutations in T-box genes are associated with numerous disease states in humans. The objective of this paper was to characterize the T(shao), a specific T-box mutation, in mice. T(shao), a short-tailed mutant mouse strain in a B6 background, was obtained by ethylnitrosourea mutagenesis. Microsatellite genomic scans mapped the location of the mutation. RT-PCR was used to amplify the identified region and the product was sequenced. DNA of the region was sequenced and scanned for mutations. Tails of T(shao) mice were mostly curly with tail length ranging from less than 1 cm (tail bud) to half of the normal length. T(shao) presented single dominance gene inheritance, and homozygous mutant mice died approximately at E10. Scans of the F2 generation mapped the mutant gene to chromosome 17, near D17Mit143. The Brachyury (T) gene was identified as a potential candidate gene in this location. To confirm this, RT-PCR was performed on RNA from intercrossed 8.5-day embryos, and products were sequenced. A 67-nucleotide deletion in exon 2 of the mutant T gene was identified. Further sequencing of the genomic DNA from this region identified a T to A transversion at the 67th nucleotide of exon 2. The T(shao) mutation is a result of a deletion in exon 2 causing the early termination and loss of function of protein encoded by the T gene, manifesting as a short tail phenotype.

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The human T locus and spina bifida risk

Cited by 27 publications

References 62 publications

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

Analysis of the fibroblastic growth factor receptor-RAS/RAF/MEK/ERK-ETS2/brachyury signalling pathway in chordomas

Part 2

Identification of a Novel Mouse Brachyury (T) Allele Causing a Short Tail Mutation in Mice

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