Digenic Inheritance of Mutations in FOXC1 and PITX2: Correlating Transcription Factor Function and Axenfeld-Rieger Disease Severity
Digenic Inheritance of Mutations in FOXC1 and PITX2: Correlating Transcription Factor Function and Axenfeld-Rieger Disease Severity
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DOI：
10.1002/humu.21550
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发表时间：
2011-10-01
期刊：
影响因子：
3.9
通讯作者：
Sowden, Jane C.
中科院分区：
文献类型：
--
作者：
Kelberman, Daniel;Islam, Lily;Sowden, Jane C.
先前已经在阿森菲尔德-里格综合征(AR)患者中发现了影响转录因子基因PITX2或FOXC1之一的致病突变。我们发现了一个分离PITX2(p.Ser233Leu)和FOXC1(c.609delC)新突变的家族。受影响最严重的个体，表现为非典型表型的角膜混浊、晶状体脱出、持续性增生性玻璃体(PHPV)以及随后的双侧视网膜脱离，这两个基因都有遗传突变，而单一杂合子突变导致轻微的AR表型。这种双基因遗传尚属首次报道。通过分析每个基因的同源靶点，我们发现FOXC1和PITX2在体外可以独立地调节各自和彼此的靶基因启动子，而不表现出协同作用。任何一个基因的突变都不同程度地降低了FOXO1和PLOD1启动子上的转录激活程度，而这两个突变组合显示的激活水平最低。这些数据表明，当一个因子的补偿活性受到损害时，另一个因子可能会减轻发育异常的表型影响，但两个转录因子的活性降低会增加疾病的严重性。这暗示了表型变异的一种未被报道的机制，即单一突变导致轻微的AR表型，而双基因遗传增加表型的严重性。嗡嗡作响32：1144-1152,2011。(C)2011年Wiley-Liss，Inc.
Disease-causing mutations affecting either one of the transcription factor genes, PITX2 or FOXC1, have been previously identified in patients with Axenfeld-Rieger syndrome (AR). We identified a family who segregate novel mutations in both PITX2 (p.Ser233Leu) and FOXC1 (c.609delC). The most severely affected individual, who presented with an atypical phenotype of corneal opacification, lens extrusion, persistent hyperplastic primary vitreous (PHPV), and subsequent bilateral retinal detachment, inherited mutations in both genes, whereas the single heterozygous mutations caused mild AR phenotypes. This is the first report of such digenic inheritance. By analyzing cognate targets of each gene, we showed that FOXC1 and PITX2 can independently regulate their own and each other's target gene promoters and do not show synergistic action in vitro. Mutation in either gene caused reduced transcriptional activation to different extents on the FOXO1 and PLOD1 promoters, whereas both mutations in combination showed the lowest level of activation. These data show how the compensatory activity of one factor, when the other is impaired, may lessen the phenotypic impact of developmental anomalies, yet reduced activity of both transcription factors increased disease severity. This suggests an under-reported mechanism for phenotypic variability whereby single mutations cause mild AR phenotypes, whereas digenic inheritance increases phenotypic severity. Hum Mutat 32:1144-1152, 2011. (C) 2011 Wiley-Liss, Inc.