A screen for mutations in human homologues of mice exencephaly genes Tfap2α and Msx2 in patients with neural tube defects

Karolin Stegmann, Julia Boecker, Brbel Richter, Valeria Capra, Richard H. Finnell, Ernestine T K N Ngo, Elisabeth Strehl, August Ermert, Manuela C. Koch

Research output: Contribution to journalArticle

Abstract

Background: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2α and Msx2, which are expressed in the developing neural tube. Methods: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2α and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRα, and PAX1 already shown to be related to NTD. Results: Two TFAP2α point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2α and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2α polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% Cl 0.57-5.39). Conclusions: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.

Original languageEnglish
Pages (from-to)167-175
Number of pages9
JournalTeratology
Volume63
Issue number5
DOIs
Publication statusPublished - 2001

Fingerprint

Neural Tube Defects
Genes
Defects
Mutation
Polymorphism
Mutant Strains Mice
Spina Bifida Cystica
Anencephaly
Encephalocele
Neural Tube
Protein Biosynthesis
Nucleic Acids
Pedigree
Conformations
Point Mutation
Codon
Association reactions
Amino Acids
Alleles
Messenger RNA

ASJC Scopus subject areas

  • Developmental Biology
  • Embryology
  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Stegmann, K., Boecker, J., Richter, B., Capra, V., Finnell, R. H., Ngo, E. T. K. N., ... Koch, M. C. (2001). A screen for mutations in human homologues of mice exencephaly genes Tfap2α and Msx2 in patients with neural tube defects. Teratology, 63(5), 167-175. https://doi.org/10.1002/tera.1031

A screen for mutations in human homologues of mice exencephaly genes Tfap2α and Msx2 in patients with neural tube defects. / Stegmann, Karolin; Boecker, Julia; Richter, Brbel; Capra, Valeria; Finnell, Richard H.; Ngo, Ernestine T K N; Strehl, Elisabeth; Ermert, August; Koch, Manuela C.

In: Teratology, Vol. 63, No. 5, 2001, p. 167-175.

Research output: Contribution to journalArticle

Stegmann, K, Boecker, J, Richter, B, Capra, V, Finnell, RH, Ngo, ETKN, Strehl, E, Ermert, A & Koch, MC 2001, 'A screen for mutations in human homologues of mice exencephaly genes Tfap2α and Msx2 in patients with neural tube defects', Teratology, vol. 63, no. 5, pp. 167-175. https://doi.org/10.1002/tera.1031
Stegmann, Karolin ; Boecker, Julia ; Richter, Brbel ; Capra, Valeria ; Finnell, Richard H. ; Ngo, Ernestine T K N ; Strehl, Elisabeth ; Ermert, August ; Koch, Manuela C. / A screen for mutations in human homologues of mice exencephaly genes Tfap2α and Msx2 in patients with neural tube defects. In: Teratology. 2001 ; Vol. 63, No. 5. pp. 167-175.
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abstract = "Background: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2α and Msx2, which are expressed in the developing neural tube. Methods: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2α and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRα, and PAX1 already shown to be related to NTD. Results: Two TFAP2α point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2α and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2α polymorphism were at a slightly increased risk of NTD (OR 1.71; 95{\%} Cl 0.57-5.39). Conclusions: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.",
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T1 - A screen for mutations in human homologues of mice exencephaly genes Tfap2α and Msx2 in patients with neural tube defects

AU - Stegmann, Karolin

AU - Boecker, Julia

AU - Richter, Brbel

AU - Capra, Valeria

AU - Finnell, Richard H.

AU - Ngo, Ernestine T K N

AU - Strehl, Elisabeth

AU - Ermert, August

AU - Koch, Manuela C.

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N2 - Background: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2α and Msx2, which are expressed in the developing neural tube. Methods: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2α and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRα, and PAX1 already shown to be related to NTD. Results: Two TFAP2α point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2α and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2α polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% Cl 0.57-5.39). Conclusions: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.

AB - Background: Very little is known about the identity of genetic factors involved in the complex etiology of nonsyndromic neural tube defects (NTD). Potential susceptibility genes have emerged from the vast number of mutant mouse strains displaying NTD. Reasonable candidates are the human homologues of mice exencephaly genes Tfap2α and Msx2, which are expressed in the developing neural tube. Methods: A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2α and MSX2 was performed for 204 nonsyndromic NTD patients including cases of anencephaly (n = 10), encephalocele (n = 8), and spina bifida aperta, SBA (n = 183). A selected number of SBA patients was additionally tested for specific mutations in MTHFD, FRα, and PAX1 already shown to be related to NTD. Results: Two TFAP2α point mutations in individual SBA patients were silent on the amino acid level (C308C, T396T). On nucleic acid level, these mutations change evolutionary conserved codons and thus may influence mRNA processing and translation efficiency. One SBA patient displayed an exonic 9-bp deletion in MSX2 leading to a shortened and possibly less functional protein. None of these mutations was found in 222 controls. Seven polymorphisms detected in TFAP2α and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2α polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% Cl 0.57-5.39). Conclusions: Although several new genetic variants were found in TFAP2 and MSX2, no statistically significant association was found between NTD cases and the new alleles or their combinations. Further studies are necessary to finally decide if these gene variants may have acted as susceptibility factors in our individual cases.

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