Chordin is a modifier of tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse.
Chordin is a modifier of tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse.
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DOI：
10.1371/journal.pgen.1000395
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发表时间：
2009-02
期刊：
影响因子：
4.5
通讯作者：
Klingensmith, John
中科院分区：
文献类型：
--
作者：
Choi, Murim;Klingensmith, John
TBX 1的点突变可以重现22 q11缺失综合征（22 q11 DS）的许多结构缺陷，通常与22q1.2的染色体缺失相关。22 q11 DS通常包括特定的心脏和咽器官异常，但特征性颅面缺陷的存在差异很大。即使在具有单个TBX 1点突变但没有细胞学缺失的家庭成员中，腭裂和低位耳可能存在也可能不存在。从理论上讲，这种差异可能取决于一个未识别的第二部位病变，该病变改变了TBX 1缺乏的颅面后果。我们目前的证据表明，这样一个位点在小鼠模型。据报道，脊索蛋白的突变可导致重现22 q11 DS的严重缺陷，我们发现这高度依赖于遗传背景。在一个近交系中，其中chordin-/-是完全渗透，我们发现了一个紧密相连的，强大的修饰符-突变Tbx 1内含子造成严重的剪接缺陷。如果没有它，缺乏腱蛋白会导致下颌发育不全的低发生率，但不会导致心脏或胸部器官畸形。这种亚型Tbx 1等位基因本身导致类似22 q11 DS的缺陷，但具有标志性颅面畸形的低突变率，除非脊索蛋白突变。因此，脊索蛋白是Tbx 1突变的颅面异常的修饰剂，证明了与22 q11 DS相关的表型的特定子集的第二位点修饰剂的存在。一系列结构畸形与22 q11缺失综合征（22 q11 DS）相关，该综合征通常与染色体22q11.2处的微缺失相关。心血管、咽部和颅面结构的缺陷是可变的，但这种可变性的基础尚不清楚。TBX 1（通常缺失的区域内的基因）中的突变可以重现22q11.2缺失的结构异常。然而，即使在具有单个TBX 1点突变的家庭成员中，颅面缺陷也是可变的。从理论上讲，这种差异可能取决于一个未知的，第二个网站的病变，修改颅面TBX 1缺陷的后果。我们在小鼠中发现了这样一个位点。在某些菌株中，缺乏脊索蛋白基因导致类似于严重的22 q11 DS的表型，也见于缺乏Tbx 1的小鼠。我们发现，脊索蛋白的表型依赖于一个紧密相连的，强大的修改器-一个神秘的，部分功能的突变Tbx 1。没有它，缺乏腱蛋白有时会导致下颌骨截断，但没有心脏或胸部器官畸形。这种新的Tbx 1等位基因本身导致类似22 q11 DS的缺陷，但具有低频率的标志性颅面畸形，除非脊索蛋白突变。因此，脊索蛋白是Tbx 1突变的颅面异常的修饰剂，证明了与22 q11 DS相关的表型的特定子集的第二位点修饰剂的存在。
Point mutations in TBX1 can recapitulate many of the structural defects of 22q11 deletion syndromes (22q11DS), usually associated with a chromosomal deletion at 22q1.2. 22q11DS often includes specific cardiac and pharyngeal organ anomalies, but the presence of characteristic craniofacial defects is highly variable. Even among family members with a single TBX1 point mutation but no cytological deletion, cleft palate and low-set ears may or may not be present. In theory, such differences could depend on an unidentified, second-site lesion that modifies the craniofacial consequences of TBX1 deficiency. We present evidence for such a locus in a mouse model. Null mutations of chordin have been reported to cause severe defects recapitulating 22q11DS, which we show are highly dependent on genetic background. In an inbred strain in which chordin−/− is fully penetrant, we found a closely linked, strong modifier—a mutation in a Tbx1 intron causing severe splicing defects. Without it, lack of chordin results in a low penetrance of mandibular hypoplasia but no cardiac or thoracic organ malformations. This hypomorphic Tbx1 allele per se results in defects resembling 22q11DS but with a low penetrance of hallmark craniofacial malformations, unless chordin is mutant. Thus, chordin is a modifier for the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of the phenotypes associated with 22q11DS. A range of structural malformations is associated with 22q11 deletion syndrome (22q11DS), which is usually associated with microdeletions at chromosome 22q11.2. Variable defects in cardiovascular, pharyngeal, and craniofacial structures occur, but the basis for such variability is unknown. Mutations in TBX1, a gene within the region typically deleted, can recapitulate the structural anomalies of 22q11.2 deletions. However, even among family members with a single TBX1 point mutation, craniofacial defects are variable. In theory, such differences could depend on an unknown, second-site lesion that modifies the craniofacial consequences of TBX1 deficiency. We identify such a locus in mouse. In certain strains, lack of the chordin gene results in a phenotype resembling severe 22q11DS, also seen in mice lacking Tbx1. We find that the chordin phenotype depends on a closely linked, strong modifier—a cryptic, partial-function mutation in Tbx1. Without it, lack of chordin sometimes results in mandibular truncations but no cardiac or thoracic organ malformations. This novel Tbx1 allele per se results in defects resembling 22q11DS, but with a low frequency of hallmark craniofacial malformations, unless chordin is mutant. Thus chordin is a modifier for the craniofacial anomalies of Tbx1 mutations, demonstrating the existence of a second-site modifier for a specific subset of phenotypes associated with 22q11DS.
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