Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/deI22q11 syndromes
Genetic factors are major determinants of phenotypic variability in a mouse model of the DiGeorge/deI22q11 syndromes
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DOI：
10.1073/pnas.201127298
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发表时间：
2001-09-25
影响因子：
11.1
通讯作者：
Lindsay, EA
中科院分区：
文献类型：
--
作者：
Taddei, I;Morishima, M;Lindsay, EA
del 22 q11综合征与高度可变的表型相关，尽管在大多数患者中引起该疾病的染色体缺失是一致的。df 1/+小鼠，其模型del 22 q11，表现出减少的心血管缺陷的发生率类似于在缺失患者中观察到的，但没有其他del 22 q11样的发现。心血管缺陷的发生率降低是由突变胚胎从第四咽弓动脉生长异常中恢复的能力引起的，该异常在早期胚胎中是完全渗透的。在这里，我们表明遗传背景通过影响胚胎恢复过程对心血管缺陷的发生率有重要影响。这种效应不能用单倍体位点的等位基因变异来解释，很可能是由基因组中其他地方的遗传修饰剂引起的。我们还表明，遗传因素控制扩展的Df 1/+表型，包括胸腺和甲状旁腺异常，建立DO小鼠作为模型的三个主要特征的人类del 22 q11综合征的遗传分析。我们发现，在Df 1/+小鼠中，与人类患者一样，心脏和胸腺表型的表达基本上是相互独立的，这表明它们可能受到不同遗传修饰剂的控制。这些数据为我们理解del 22 q11综合征患者的表型变异性及其遗传解剖工具提供了一个框架。
The del22q11 syndrome is associated with a highly variable phenotype despite the uniformity of the chromosomal deletion that causes the disease in most patients. Df1/+ mice, which model del22q11, present with reduced penetrance of cardiovascular defects similar to those seen in deleted patients but not with other del22q11-like findings. The reduced penetrance of cardiovascular defects is caused by the ability of mutant embryos to recover from a fourth pharyngeal arch artery growth abnormality that is fully penetrant in early embryos. Here we show that genetic background has a major effect on penetrance of cardiovascular defects by affecting this embryonic recovery process. This effect could not be explained by allelic variation at the haploid locus, and it is likely to be caused by genetic modifiers elsewhere in the genome. We also show that genetic factors control extension of the Df1/+ phenotype to include thymic and parathyroid anomalies, establishing the DO mouse as a model for the genetic analysis of three major features of human del22q11 syndrome. We found that in Df1/+ mice, as in human patients, expression of the heart and thymic phenotypes are essentially independent from each other, suggesting that they may be controlled by different genetic modifiers. These data provide a framework for our understanding of phenotypic variability in patients with del22q11 syndrome and the tools for its genetic dissection.