Heterozygous mutations of OTX2 cause severe ocular malformations
Heterozygous mutations of OTX2 cause severe ocular malformations
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DOI：
10.1086/430721
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发表时间：
2005-06-01
影响因子：
9.8
通讯作者：
Hanson, IM
中科院分区：
文献类型：
--
作者：
Ragge, NK;Brown, AG;Hanson, IM
人眼的主要畸形，包括小眼症和无眼症，是在家族中反复出现的表型的例子，但通常没有明确的孟德尔遗传模式。因此，通过映射来定义位点很少可行。使用候选基因方法，我们在8个眼部畸形家庭中发现了同源盒基因OTX2的杂合编码区变化。人类胚胎中OTX2的表达模式与患者观察到的眼睛表型一致，从双侧眼失症到类似Leber先天性黑内障和色素视网膜病变的视网膜缺陷。磁共振成像扫描显示视神经，视交叉，在某些情况下，大脑的缺陷。在两个家庭中，突变似乎是在受严重影响的后代中从头发生的，而在另外两个家庭中，突变是从淋体镶嵌亲本遗传的。来自这四个家族的数据支持OTX2杂合功能丧失突变导致眼部畸形的简单模型。另外四个家族表现出复杂的遗传模式，这表明OTX2突变本身可能不会导致一致的表型。高发病率的镶嵌和降低外显率有遗传咨询的意义。
Major malformations of the human eye, including microphthalmia and anophthalmia, are examples of phenotypes that recur in families yet often show no clear Mendelian inheritance pattern. Defining loci by mapping is therefore rarely feasible. Using a candidate-gene approach, we have identified heterozygous coding-region changes in the homeobox gene OTX2 in eight families with ocular malformations. The expression pattern of OTX2 in human embryos is consistent with the eye phenotypes observed in the patients, which range from bilateral anophthalmia to retinal defects resembling Leber congenital amaurosis and pigmentary retinopathy. Magnetic resonance imaging scans revealed defects of the optic nerve, optic chiasm, and, in some cases, brain. In two families, the mutations appear to have occurred de novo in severely affected offspring, and, in two other families, the mutations have been inherited from a gonosomal mosaic parent. Data from these four families support a simple model in which OTX2 heterozygous loss-of-function mutations cause ocular malformations. Four additional families display complex inheritance patterns, suggesting that OTX2 mutations alone may not lead to consistent phenotypes. The high incidence of mosaicism and the reduced penetrance have implications for genetic counseling.