Quantitative trait loci affecting phenotypic variation in the vacuolated lens mouse mutant, a multigenic mouse model of neural tube defects

摘要

The vacuolatedlens (vl) mouse mutant arose spontaneously on the C3H/HeSn back-ground and exhibits neural tube defects (NTDs), congenital cataract,and occasionally a white belly spot. We previously reported that 1) thevl phenotypes are due to a mutation in an orphan G protein-coupledreceptor (GPCR), Gpr161; 2) the penetrance of the vl NTD andcataract phenotypes are affected by genetic background, allowingthree unlinked quantitative trait loci (QTL) to be mapped (modifiers ofvacuolated lens, Modvl1-3); and 3) phenotype-based bioinformaticsfollowed by genetic and molecular analysis identified a lens-specifictranscription factor that contributes to the cataract-modifying effect ofModvl3. We now extend this analysis in three ways. First, using theGpr161 mutation to unequivocally identify mutant adults and em-bryos, we determined that ～50% of vl/vl NTD-affected embryos dieduring development. Second, the MOLF/Ei genetic background sup-presses this embryonic lethality but increases the incidence of theadult belly spot phenotype. Additional QTL analysis was performed,and two novel modifiers were mapped [Modvl4, logarithm of oddsratio (LOD) 4.4; Modvl5, LOD 5.0]. Third, phenotype-based bioin-formatics identified candidate genes for these modifiers including twoGPCRs that cause NTD or skin/pigmentation defects (Modvl4: Friz-zled homolog 6; Modvl5: Melanocortin 5 receptor). Because GPCRsform oligomeric complexes, these genes were resequenced and non-synonymous coding variants were identified. Bioinformatics and pro-tein modeling suggest that these variants may be functional. Ourstudies further establish vl as a multigenic mouse model for NTDs andidentify additional QTL that interact with Gpr161 to regulate neuru-lation.