The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA.
Exp Eye Res. 2014 Jan;118:30-5. doi: 10.1016/j.exer.2013.10.020. Epub 2013 Nov 4.
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.
鉴定能改变小鼠模型病理性眼部表型的基因，可能有助于我们深入了解疾病机制，并为新的治疗策略提供依据。本研究鉴定了影响纯合型 Mfrp(rd6) 小鼠感光细胞丢失的修饰基因座，该基因敲除型小鼠表现出缓慢进展的感光细胞变性。我们对 63 只 20 周龄纯合型 Mfrp(rd6) 小鼠（B6.C3Ga-Mfrp(rd6)/J×CAST/EiJ）F1 杂交后代进行了分析，这些小鼠视网膜外核层的感光细胞数量存在差异。利用单核苷酸多态性标记物对这些小鼠进行了基因分型，并通过数量性状基因座（QTL）分析将基因型与表型相关联，以定位修饰基因座。全基因组扫描发现，CAST/EiJ 染色体 1 上存在一个具有统计学意义的、保护性候选修饰基因座，染色体 6 和 11 上也存在一些提示性修饰基因座。对三基因座模型的多元回归分析表明，染色体 1 和 6 上的修饰基因座共同解释了 26%的观察到的表型变异，而染色体 11 上的修饰基因座仅额外解释了 4%。我们的研究结果表明，Mfrp(rd6) 小鼠视网膜退行性病变的严重程度取决于品系的遗传背景，CAST/EiJ 染色体 1 上的一个重要修饰基因座可以保护 Mfrp(rd6) 相关的感光细胞丢失。
