X-linked situs abnormalities result from mutations in ZIC3
X-linked situs abnormalities result from mutations in ZIC3
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DOI：
10.1038/ng1197-305
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发表时间：
1997-11-01
期刊：
影响因子：
30.8
通讯作者：
Casey, B
中科院分区：
文献类型：
--
作者：
Gebbia, M;Ferrero, GB;Casey, B
脊椎动物沿着左右（LR）身体轴沿着不对称地定位胸部和腹部的未配对器官。每一个结构相对于中线非随机地位于一个整体位置，称为孤立点，在人类中，心脏、胃和脾的位置一直在左边。LR轴发育异常可导致单个器官位置的随机化（部位不明确）或所有偏侧结构的镜像反转（部位反转）（1）。以前，我们通过在单个家族（LR 1）中的连锁分析和通过检测不相关的可疑位点男性（家族LR 2;参考文献2，3）中的缺失，将人类位点异常的基因座HTX 1定位到Xq 26. 2。从这个染色体区域，我们已经定位克隆ZIC 3，一个基因编码一个假定的锌指转录因子。一个移码，两个错义和两个无义突变已被确定在家族性和散发性的网站模棱两可。移码等位基因也与一些杂合子女性中的位点倒置相关，这表明ZIC 3在LR轴形成的最早阶段起作用。ZIC 3以前没有涉及脊椎动物LR轴发育，是第一个明确与人类位点异常相关的基因。
Vertebrates position unpaired organs of the chest and abdomen asymmetrically along the left-right (LR) body axis. Each structure comes to lie non-randomly with respect to the midline in an overall position designated sites solitus, exemplified in humans by placement of the heart, stomach and spleen consistently to the left. Aberrant LR axis development can lead to randomization of individual organ position (sites ambiguus) or to mirror-image reversal of all lateralized structures (sites inversus)(1). Previously we mapped a locus for sites abnormalities in humans, HTX1, to Xq26.2 by linkage analysis in a single family (LR1) and by detection of a deletion in an unrelated sites ambiguus male (Family LR2; refs 2,3). From this chromosomal region we have positionally cloned ZIC3, a gene encoding a putative zinc-finger transcription factor. One frameshift, two missense and two nonsense mutations have been identified in familial and sporadic sites ambiguus. The frameshift allele is also associated with sites inverses among some heterozygous females, suggesting that ZIC3 functions in the earliest stages of LR-axis formation. ZIC3, which has not been previously implicated in vertebrate LR-axis development, is the first gene unequivocally associated with human sites abnormalities.