title: A screen for mutations in human homologues of mice exencephaly genes Tfap2alpha and Msx2 in patients with neural tube defects.
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 Tfap2alpha and Msx2, which are expressed in the developing neural tube.
  
  
  METHODS
  A single-strand conformation analysis (SSCA) mutation screen of the coding sequences of TFAP2alpha 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, FRalpha, and PAX1 already shown to be related to NTD.
  
  
  RESULTS
  Two TFAP2alpha 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 TFAP2alpha and MSX2 were equally distributed in patients and controls. Patients with combined heterozygosity of an exonic MSX2 and an intronic TFAP2alpha polymorphism were at a slightly increased risk of NTD (OR 1.71; 95% CI 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.
authors.affiliation: Medizinisches Zentrum für Humangenetik, Philipps-Universität Marburg, 35033 Marburg, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Stegmann
authors.forename: J
authors.initials: J
authors.lastname: Boecker
authors.forename: B
authors.initials: B
authors.lastname: Richter
authors.forename: V
authors.initials: V
authors.lastname: Capra
authors.forename: R H
authors.initials: RH
authors.lastname: Finnell
authors.forename: E T
authors.initials: ET
authors.lastname: Ngo
authors.forename: E
authors.initials: E
authors.lastname: Strehl
authors.forename: A
authors.initials: A
authors.lastname: Ermert
authors.forename: M C
authors.initials: MC
authors.lastname: Koch
mesh_terms: D000483:Alleles; D000757:Anencephaly / Q000235:genetics; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D003062:Codon; D018076:DNA, Complementary / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D004677:Encephalocele / Q000235:genetics; D005091:Exons; D058973:Folate Receptors, GPI-Anchored; D005492:Folic Acid / Q000378:metabolism; D017353:Gene Deletion; D005838:Genotype; D018398:Homeodomain Proteins; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009436:Neural Tube Defects / Q000235:genetics*; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D011956:Receptors, Cell Surface; D016135:Spinal Dysraphism / Q000235:genetics; D050656:Transcription Factor AP-2; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D003062:Codon; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D058973:Folate Receptors, GPI-Anchored; D018398:Homeodomain Proteins; C084119:MSX2 protein; D011956:Receptors, Cell Surface; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D005492:Folic Acid