Modifier locus for exencephaly in Cecr2 mutant mice is syntenic to the 10q25.3 region associated with neural tube defects in humans

Physiol Genomics. 2007 Oct 22;31(2):244-51. doi: 10.1152/physiolgenomics.00062.2007. Epub 2007 Jul 10.


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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chromosome Mapping
  • Chromosomes, Human, Pair 10 / genetics
  • Crosses, Genetic
  • Epistasis, Genetic*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Intercellular Signaling Peptides and Proteins / deficiency
  • Intercellular Signaling Peptides and Proteins / genetics*
  • Lod Score
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Mutant Strains
  • Microfilament Proteins / genetics
  • Neural Tube Defects / embryology
  • Neural Tube Defects / genetics*
  • Neural Tube Defects / pathology
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors / genetics
  • Penetrance
  • Quantitative Trait Loci
  • Species Specificity
  • Transcription Factors


  • CECR2 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • PAX3 Transcription Factor
  • Paired Box Transcription Factors
  • Shrm protein, mouse
  • Transcription Factors
  • Pax3 protein, mouse