FRalpha, BMP4 und humanes T-Genals Kandidatengene für Neuralrohrdefekte
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Philipps-Universität Marburg
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Abstract
Neural tube defects (NTDs) are likely to result from an
interaction of several genes and environmental factors.
A role for genetic factors is supported by the finding
that first degree relatives of NTD patients have a significantly
increased recurrence risk. Since periconceptional folic acid
supplementation of the maternal diet has been shown to have
a preventive effect on occurrence and recurrence of the
malformation, one contributing factor is believed to involve an
altered folate metabolism.
Other potential candidate genes for human NTDs are
offered by animal models. NTDs have been observed in a variety
of mutant mice, spontaneously arisen or genetically
engineered. The secreted polypeptide Bmp4 was chosen
from the candidate lists as it is a neurulation gene:
Bmp4 is expressed in the dorsal epidermal ectoderm, posterior
mesoderm and the presumptive neural crest cells.
Targeted inactivation in
mice leads to abnormal phenotypes: Bmp4 knockout mice
exhibit little mesoderm differentiation causing disorganised
structures (including a small neural plate and cranially
open folds
Our study with spina bifida aperta (SBA)
patients revealed single point mutations in BMP 4 that
may have acted as susceptibility factors in the individual
cases. Interestingly, an association study provides evidence
for a genotype disequilibrium between SBA patients and
controls for the BMP4 polymorphism 455T>C (V152A).
The frequency of the heterozygous 455T>C genotype is
lower in cases than in controls. A possible explanation is
that BMP4 heterozygosity at this site is a protective factor
in the normal population, although this hypothesis cannot
be proven to date.
One of the candidate genes for human NTDs,
the murine Brachyury gene (T gene), was recognised by virtue
of its mutant phenotype. Mice that are homozygous for null
mutations in Brachyury die in midgestation because of abnormalities
in notochord and defects in other mesoderm derived
structures. Heterozygous mice have short tails, notochord
anomalies, and fusion of neural tube and gut in the caudal
region. Studies of T gene expression pattern show that it is
maintained in those cells that are absent in mutant mouse
embryos, early stage mesoderm, tailbud, and notochord.
Brachyury encodes a DNA binding protein that functions as
a transcription activator.
Genotyping for the TIVS7 three allele polymorphism was performed
using primers and single strand conformation analysis
(SSCA) as previously described. We detected the two
common alleles corresponding to a T (allele 1) to C (allele 2)
single base exchange at position 79 bp downstream from the
5¢ end of intron 7. The rare third allele was not detected in our
population. Genotypes resulting from the nucleotide exchanges
were confirmed by sequencing several independent
subjects.
We found TIVS7 heterozygosity (homozygosity of allele 2) in 44.3% (7.6%) of
cases and in 40.2% (8.3%) of controls (table 1). Genotype frequencies
in cases and controls were compared using Cochran-
Armitage trend tests. There was no significant difference in
TIVS7 genotype distribution in our sample (p=0.70). Analysis
of 101 trios (father, mother, SBA child) showed no transmission
disequilibrium for the TIVS7-2 allele (transmitted:nontransmitted
45:49). A p value of 0.68 was calculated using the
exact version of McNemar’s test.17
In conclusion, our results do not indicate an increased risk for
sporadic SBA among homozygotes or heterozygotes for the
human T TIVS7 genotypes. These data are supported by previous
studies and therefore it is questionable if this
polymorphism plays an important role in the susceptibility for
sporadic NTD.
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Dates
Created: 2007Issued: 2007-09-20Updated: 2011-08-10
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
Human TFolsäurerezeptor alphahumanes T-GenBMP 4Folate receptor alphaNeural tube defect
DFG-subjects
Spina bifidaKnochen-Morphogenese-ProteineMedullarrohrdefekt
DDC-Numbers
610
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Helvogt, Almut: FRalpha, BMP4 und humanes T-Genals Kandidatengene für Neuralrohrdefekte. : Philipps-Universität Marburg 2007-09-20. DOI: https://doi.org/10.17192/z2007.0583.
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This item has been published with the following license: In Copyright