Modvl1^C3H/HeSnJ
QTL Variant Detail

Summary

• QTL variant: Modvl1^C3H/HeSnJ
• Name: modifier of vacuolated lens 1; C3H/HeSnJ
• MGI ID: MGI:3793308
• QTL: Modvl1 Location: Chr5:79650568-79650688 bp Genetic Position: Chr5, Syntenic

Variant origin

• Strain of Specimen: C3H/HeSnJ

Variant description

• Allele Type: QTL
• Mutation: Undefined
• Mutation details: This allele is a modifier of Gpr161^vl and confers increased spina bifida incidence compared to C57BL/6J. (J:131929)
• Inheritance: Dominant

Notes

Mapping and Phenotype information for this QTL, its variants and associated markers

J:131929

The Gpr161^vl mutation spontaneously arose on the C3H/HeSnJ genetic background and results in congenital cataracts and neural tube defects (spina bifida). Spina bifida affects 50% of C3H/HeSnJ-Gpr161^vl embryos and is lethal in utero. Surviving mice display congenital cataracts without spina bifida. However, crossing the mutation to other inbred strains results in phenotypic variation. Homozygous mutant F2 progeny derived from C3H/SnJ-Gpr161^vl and MOLF/EiJ have a significantly decreased incidence of cataracts, indicating the presence of genetic modifiers. In addition, 50% of homozygous mutant F2 progeny derived from C3H/SnJ-Gpr161^vl and CAST/EiJ or C57BL/6J display spina bifida and hindlimb paralysis. Linkage analysis was performed on all 3 sets ofF2 intercrosses (n=86 to 132) to identify genetic modifiers of Gpr161^vl. Panels of 60-80 polymorphic markers were used for genome scan.

Significant linkage to spina bifida susceptibility mapped to 44 cM on mouse Chromosome 5 in the (C3H/HeSnJ-Gpr161^vl x C57BL/6J)F2 population. This locus is linked to D5Mit309 (LOD=3.7) and is designated Modvl1 (modifier of vacuolated lens 1). The 95% confidence interval spans 38 cM - 50 cM. C3H/HeSnJ-derived alleles at Modvl1 confer increased spina bifida incidencein Gpr161^vl homozygous F2 animals with a dominant mode of inheritance. Modvl1 explains 15.9% of the spina bifida variance in this F2 cross.

Significant linkage to spina bifida susceptibility mapped to 26 cM on mouse Chromosome 1 near D1Mit236 (LOD=3.3). This locus has a 95% confidence interval spanning 0 cM - 36 cM and is named Modvl2 (modifier of vacuolated lens 2). Modvl2 was identified in the (C3H/HeSnJ-Gpr161^vl x CAST/EiJ)F2 population. C3H/HeSnJ-derived alleles confer increased spina bifida incidence in Gpr161^vl homozygous F2 animals with an additive mode of inheritance. Modvl2 explains 13.1% of the spina bifida variance in this F2 cross.

A modifier of cataract susceptibility mapped to 51 cM on mouse Chromosome 4 near D4Mit168 (LOD=4.2) in the (C3H/HeSnJ-Gpr161^vl x MOLF/EiJ)F2 population. This locus is named Modvl3 (modifier of vacuolated lens 3) with a 95% confidence interval spanning 45 cM - 61 cM. MOLF/EiJ-derived alleles confer increased cataract incidence in Gpr161^vl homozygous F2 animals. The mode of inheritance appears additive. Modvl3 explains 9.9% of the cataract variance in this F2 cross.

Foxe3 at 49.6 cM on chromosome 4 was identified as a Modvl3 candidate gene. Authors cite four lines of evidence that Foxe3 is the qualitative trait gene responsible for Modvl3. First, Foxe3 is expressed in the developing lens and mutations in mice and humans are associated with cataracts and other lens-associated diseases. Second, a non-conservative amino acid change at position 23 results ina proline (MOLF/EiJ) to leucine (C3H/HeSnJ) substitution. This change is predicted to alter the Foxe3 protein structure. Third, BALB/c strain carries the C3H/HeSnJ-like leucine allele at aa23 of Foxe3 and crosses with C3H/HeSnJ-Gpr161^vl would not be expected to modify the cataract phenotype. As predicted, homozygous mutant (C3H/HeSnJ-Gpr161^vl x BALB/c)F2 animals displayed 100% cataract incidence. Fourth, in vitro functional assays showed the Foxe3 23-proline allele displays lower activity compared tothe Foxe3 23-leucine allele.

References

• Original: J:131929 Matteson PG, et al., The orphan G protein-coupled receptor, Gpr161, encodes the vacuolated lens locus and controls neurulation and lens development. Proc Natl Acad Sci U S A. 2008 Feb 12;105(6):2088-93
• All: 1 reference(s)