title: Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans.
abstract: Neural tube defects (NTDs), the second most common birth defect in humans, are multifactorial with complex genetic and environmental causes, although the genetic factors are almost completely unknown. In mice, >100 single gene mutations cause NTDs; however, the penetrance in many of these single gene mutant lines is highly dependent on the genetic background. We previously reported that a homozygous Cecr2 mutation on a BALB/c background causes exencephaly at a frequency of 74% compared with 0% on an FVB/N background. We now report that a major genetic modifier on chromosome 19, mapped using whole genome linkage analysis, increases the relative risk of exencephaly by 3.74 times in homozygous BALB embryos vs. BALB/FVB heterozygotes. Scanning electron microscopy revealed that the modifier does not affect the location of neural tube closure site 2, a known murine susceptibility factor for exencephaly. Crossing the Sp (Splotch) mutation in the Pax3 gene onto the FVB/N background for two generations indicated that this resistant strain also decreases the penetrance of spina bifida. The chromosome 19 modifier region corresponds to a linkage region on human chromosome 10q25.3 mapped in a whole genome scan of human NTD families. Since the FVB/N genetic background affects susceptibility to both exencephaly and spina bifida, the human homolog of the chromosome 19 modifier locus may be a better candidate for human NTD susceptibility factors than genes that when mutated actually cause NTDs in mice.
authors.affiliation: Department of Biological Sciences, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Davidson
authors.forename: Qian
authors.initials: Q
authors.lastname: Li
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.forename: Lucy R
authors.initials: LR
authors.lastname: Osborne
authors.forename: Heather E
authors.initials: HE
authors.lastname: McDermid
mesh_terms: D000818:Animals; D002874:Chromosome Mapping; D002879:Chromosomes, Human, Pair 10 / Q000235:genetics; D003433:Crosses, Genetic; D004843:Epistasis, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics*; D008126:Lod Score; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000235:genetics; D009436:Neural Tube Defects / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D019683:Penetrance; D040641:Quantitative Trait Loci; D013045:Species Specificity; D014157:Transcription Factors
chemical_list: C501837:CECR2 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D000072041:PAX3 Transcription Factor; D051761:Paired Box Transcription Factors; C402112:Shrm protein, mouse; D014157:Transcription Factors; C068686:Pax3 protein, mouse