Human T and risk for neural tube defects

Richter, Bärbel

doi:10.1136/jmg.39.3.e14

Cited by 9 publications

(7 citation statements)

References 20 publications

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“…These results suggest that this polymorpism (or a variant with which it The results of the present study are consistent with those reported by two other groups (Morrison et al 1996(Morrison et al , 1998Shields et al 2000). However, there are reports from two additional groups that have not confirmed an association between spina bifida and the TIVS7 polymorphism (Richter et al 2002;Speer et al 2002). A third negative study has also been reported (Trembath et al 1999), but it is based on very small numbers (i.e., 13 families with at least one heterozygous parent) and does not add substantially to the other published literature on this topic.…”

Section: Discussionsupporting

confidence: 93%

“…Although several singlenucleotide polymorphisms (SNPs) in the coding region of T have been reported, none have been associated with spina bifida risk (Morrison et al 1998;Speer et al 2002). The embryonic genotype for a T/C SNP (TIVS7) positioned 79 basepairs (bp) downstream of the 5′ end of intron 7 has, however, been shown to be associated with spina bifida in some (Morrison et al 1996(Morrison et al , 1998Shields et al 2000), but not all (Trembath et al 1999;Richter et al 2002;Speer et al 2002) studies. In one study, the association between the TIVS7 polymorphism and the risk of spina bifida was stronger for cases born prior to 1980 than for those born more recently (Shields et al 2000), suggesting that this association may be influenced by additional, as yet unidentified, variables.…”

Section: Introductionmentioning

confidence: 96%

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The human T locus and spina bifida risk

et al. 2004

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The transcription factor T is essential for mesoderm formation and axial development during embryogenesis. Embryonic genotype for a single-nucleotide polymorphism in intron 7 of T ( TIVS7 T/C) has been associated with the risk of spina bifida in some but not all studies. We developed a novel genotyping assay for the TIVS7 polymorphism using heteroduplex generator methodology. This assay was used to genotype spina bifida case-parent trios and the resulting data were analyzed using the transmission disequilibrium test and log-linear analyses. Analyses of these data demonstrated that heterozygous parents transmit the TIVS7-C allele to their offspring with spina bifida significantly more frequently than expected under the assumption of Mendelian inheritance (63 vs 50%, P=0.02). Moreover, these analyses suggest that the TIVS7-C allele acts in a dominant fashion, such that individuals carrying one or more copies of this allele have a 1.6-fold increased risk of spina bifida compared with individuals with zero copies. In silico analysis of the sequence surrounding this polymorphism revealed a potential target site for olfactory neuron-specific factor-1, a transcription factor expressed in the neural tube during development, spanning the polymorphic site. Several other putative, developmentally important and/or environmentally responsive transcription factor-binding sites were also identified close to the TIVS7 polymorphism. The TIVS7 polymorphism or a variant that is in linkage disequilibrium with the TIVS7 polymorphism may, therefore, play a role in T gene expression and influence the risk of spina bifida.

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Section: Discussionsupporting

confidence: 93%

Section: Introductionmentioning

confidence: 96%

The human T locus and spina bifida risk

et al. 2004

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“…Because T is expressed throughout the notochord, it is possible for the phenotypic manifestation of a mutation to occur anywhere along the vertebral column. Indeed, in mice, T mutations affect not only the tail but also more anterior vertebral segments,

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spinal cord,

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genitourinary system,

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and heart.

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Other investigators have reported the association of a C to T transition in intron 7 of T and increased risk of neural tube defects,

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but this finding has not been uniformly reproduced.

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Thus, the potential range of mutant T phenotypes must be broadened to include neural tube defects, as well as CVMs. Moreover, it is desirable to account for the absence of a clinical phenotype in the unaffected parents of our three c.1013C>T CVM subjects.…”

Section: Discussionmentioning

confidence: 99%

A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations

Ghebranious

Blank

Raggio

et al. 2008

Journal of Bone and Mineral Research

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ABSTRACT:No major susceptibility genes for sporadically occurring congenital vertebral malformations (CVM) in humans have been identified to date. Body patterning genes whose mutants cause axial skeletal anomalies in mice are candidates for human CVM susceptibility. T (also known as Brachyury) and TBX6 are critical genes needed to establish mesodermal identity. We hypothesized that mutations in T and/or TBX6 contribute to the pathogenesis of human CVMs. The complete T and TBX6 coding regions, splice junctions, and proximal 500 bp of the promoters were sequenced in 50 phenotyped patients with CVM. Three unrelated patients with sacral agenesis, Klippel-Feil syndrome, and multiple cervical and thoracic vertebral malformations were heterozygous for a c.1013C>T substitution, resulting in a predicted Ala338Val missense alteration in exon 8. A clinically unaffected parent of each patient also harbored the substitution, but the variant did not occur in an ethnically diverse, 443-person reference population. The c.1013C>T variant is significantly associated with CVM (p < 0.001). Alanine 338 shows moderate conservation across species, and valine at this position has not been reported in any species. A fourth patient harbored a c.908-8C>T variant in intron 7. This previously unreported variant was tested in 347 normal control subjects, and 11 heterozygotes and 2 T/T individuals were found. No TBX6 variants were identified. We infer that the c.1013C>T substitution is pathogenic and represents the first report of an association between a missense mutation in the T gene and the occurrence of sporadic CVMs in humans. It is uncertain whether the splice junction variant increases CVM risk. TBX6 mutations do not seem to be associated with CVM. We hypothesize that epistatic interactions between T and other developmental genes and the environment modulate the phenotypic consequences of T variants.

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“…This is exemplified by the observation that T mutations in mice affect not only the tail, but also more anterior vertebral segments, 124,125 spinal cord, 124,126 genitourinary system, 124,127 and heart 128,129 . An association between a C to T transition in intron 7 of T and increased risk of neural tube defects 130–132 has been reported by some investigators, but this finding has not been uniformly reproduced 133–135 . The potential range of mutant T phenotypes should be broadened to include neural tube defects, as well as CVM.…”

Section: Klippel−feil Syndromementioning

confidence: 99%

Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans

Giampietro

Dunwoodie

Kusumi

et al. 2008

Annals of the New York Academy of Sciences

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Vertebral malformations contribute substantially to the pathophysiology of kyphosis and scoliosis, common health problems associated with back and neck pain, disability, cosmetic disfigurement, and functional distress. This review explores (1) recent advances in the understanding of the molecular embryology underlying vertebral development and relevance to elucidation of etiologies of several known human vertebral malformation syndromes; (2) outcomes of molecular studies elucidating genetic contributions to congenital and sporadic vertebral malformation; and (3) complex interrelationships between genetic and environmental factors that contribute to the pathogenesis of isolated syndromic and nonsyndromic congenital vertebral malformation. Discussion includes exploration of the importance of establishing improved classification systems for vertebral malformation, future directions in molecular and genetic research approaches to vertebral malformation, and translational value of research efforts to clinical management and genetic counseling of affected individuals and their families.

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Human T and risk for neural tube defects

Cited by 9 publications

References 20 publications

The human T locus and spina bifida risk

The human T locus and spina bifida risk

A Missense T(Brachyury) Mutation Contributes to Vertebral Malformations

Progress in the Understanding of the Genetic Etiology of Vertebral Segmentation Disorders in Humans

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