Department of Pediatrics, Washington University School of Medicine, St. Louis, MO 63110, USA.
Circulation. 2010 Mar 23;121(11):1313-21. doi: 10.1161/CIRCULATIONAHA.109.887687. Epub 2010 Mar 8.
Mutations of the transcription factor Nkx2-5 cause pleiotropic heart defects with incomplete penetrance. This variability suggests that additional factors can affect or prevent the mutant phenotype. We assess here the role of genetic modifiers and their interactions.
Heterozygous Nkx2-5 knockout mice in the inbred strain background C57Bl/6 frequently have atrial and ventricular septal defects. The incidences are substantially reduced in the Nkx2-5(+/-) progeny of first-generation (F1) outcrosses to the strains FVB/N or A/J. Defects recur in the second generation (F2) of the F1 X F1 intercross or backcrosses to the parental strains. Analysis of >3000 Nkx2-5(+/-) hearts from 5 F2 crosses demonstrates the profound influence of genetic modifiers on disease presentation. On the basis of their incidences and coincidences, anatomically distinct malformations have shared and unique modifiers. All 3 strains carry susceptibility alleles at different loci for atrial and ventricular septal defects. Relative to the other 2 strains, A/J carries polymorphisms that confer greater susceptibility to atrial septal defect and atrioventricular septal defects and C57Bl/6 to muscular ventricular septal defects. Segregation analyses reveal that > or = 2 loci influence membranous ventricular septal defect susceptibility, whereas > or = loci and at least 1 epistatic interaction affect muscular ventricular and atrial septal defects.
Alleles of modifier genes can either buffer perturbations on cardiac development or direct the manifestation of a defect. In a genetically heterogeneous population, the predominant effect of modifier genes is health. (Circulation. 2010;121:1313-1321.)
转录因子 Nkx2-5 的突变可导致多种心脏缺陷,且不完全外显。这种变异性提示其他因素可能影响或阻止突变表型。我们在此评估遗传修饰因子及其相互作用的作用。
在近交系 C57Bl/6 背景下,杂合 Nkx2-5 基因敲除小鼠常伴有心房和室间隔缺损。在 Nkx2-5(+/-)的第一代(F1)杂交后代中,这些缺陷的发生率在 FVB/N 或 A/J 杂交种中显著降低。在 F1×F1 回交或与亲本系回交的第二代(F2)中,缺陷再次出现。对来自 5 个 F2 杂交的 >3000 个 Nkx2-5(+/-)心脏的分析表明,遗传修饰因子对疾病表现有深远影响。根据其发生率和巧合,解剖学上不同的畸形有共同的和独特的修饰因子。3 个品系在心房和室间隔缺损的不同基因座都携带易感性等位基因。与其他 2 个品系相比,A/J 携带的多态性使心房间隔缺损和房室间隔缺损的易感性增加,而 C57Bl/6 则使心肌室间隔缺损的易感性增加。分离分析显示,>或=2 个基因座影响膜性室间隔缺损的易感性,而>或=基因座和至少 1 个上位性相互作用影响心肌和心房间隔缺损。
修饰基因的等位基因可以缓冲心脏发育的干扰,也可以决定缺陷的表现。在遗传异质性人群中,修饰基因的主要作用是健康。