title: Genetic modifier loci of mouse Mfrp(rd6) identified by quantitative trait locus analysis.
abstract: The identification of genes that modify pathological ocular phenotypes in mouse models may improve our understanding of disease mechanisms and lead to new treatment strategies. Here, we identify modifier loci affecting photoreceptor cell loss in homozygous Mfrp(rd6) mice, which exhibit a slowly progressive photoreceptor degeneration. A cohort of 63 F2 homozygous Mfrp(rd6) mice from a (B6.C3Ga-Mfrp(rd6)/J × CAST/EiJ) F1 intercross exhibited a variable number of cell bodies in the retinal outer nuclear layer at 20 weeks of age. Mice were genotyped with a panel of single nucleotide polymorphism markers, and genotypes were correlated with phenotype by quantitative trait locus (QTL) analysis to map modifier loci. A genome-wide scan revealed a statistically significant, protective candidate locus on CAST/EiJ Chromosome 1 and suggestive modifier loci on Chromosomes 6 and 11. Multiple regression analysis of a three-QTL model indicated that the modifier loci on Chromosomes 1 and 6 together account for 26% of the observed phenotypic variation, while the modifier locus on Chromosome 11 explains only an additional 4%. Our findings indicate that the severity of the Mfrp(rd6) retinal degenerative phenotype in mice depends on the strain genetic background and that a significant modifier locus on CAST/EiJ Chromosome 1 protects against Mfrp(rd6)-associated photoreceptor loss.
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Jungyeon
authors.initials: J
authors.lastname: Won
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Jeremy R
authors.initials: JR
authors.lastname: Charette
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Vivek M
authors.initials: VM
authors.lastname: Philip
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Stearns
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Zhang
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Naggert
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Krebs
authors.affiliation: The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA. Electronic address: patsy.nishina@jax.org.
authors.forename: Patsy M
authors.initials: PM
authors.lastname: Nishina
mesh_terms: D000818:Animals; D004247:DNA / Q000235:genetics*; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics* / Q000378:metabolism; D005838:Genotype; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012160:Retina / Q000378:metabolism* / Q000473:pathology; D012162:Retinal Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000099274:Frizzled-Related Proteins
chemical_list: D004247:DNA; D005136:Eye Proteins; D008565:Membrane Proteins; C423368:Mfrp protein, mouse; D000099274:Frizzled-Related Proteins
keywords: MFRP; QTL analysis; eye disease; modifier genes; retinal degeneration