Holoprosencephaly due to mutations in ZIC2:: alanine tract expansion mutations may be caused by parental somatic recombination
Holoprosencephaly due to mutations in ZIC2:: alanine tract expansion mutations may be caused by parental somatic recombination
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DOI：
10.1093/hmg/10.8.791
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发表时间：
2001-04-01
影响因子：
3.5
通讯作者：
Muenke, M
中科院分区：
文献类型：
--
作者：
Brown, LY;Odent, S;Muenke, M
我们报告了一组509例染色体正常的无前脑畸形（HPE）患者的锌指转录因子基因ZIC 2突变的患病率。总体而言，我们遇到了16例HPE患者（来自15个无关家族），ZIC 2突变是3-4%病例中HPE的明显原因。7个突变是预测导致功能丧失的移码，进一步支持ZIC 2单倍不足可导致HPE的观点。一个突变是由不完美三核苷酸重复序列的扩增引起的丙氨酸序列扩增，发生在来自6个不同家族的7名患者中。在其中的三个家庭中，发现父亲显然是突变的嵌合体，我们假设这种突变可能是通过体细胞重组中的错误而产生的，这是一种极不寻常的突变机制。此外，一个突变导致单个氨基酸变化，一个突变是12个氨基酸的框内缺失。在具有ZIC 2突变的患者中观察到的中枢神经系统畸形的范围从alobar HPE（最常见）到中间纵裂融合缺陷病例。虽然严重的面部异常在HPE中很常见，但所有ZIC 2突变的患者都有相对正常的面部，这表明ZIC 2突变在没有面部畸形的HPE病例中占很大比例。
We report on the prevalence of mutations in the zinc finger transcription factor gene, ZIC2, in a group of 509 unrelated individuals with isolated holoprosencephaly (HPE) and normal chromosomes, Overall, we encountered 16 HPE patients (from 15 unrelated families) with ZIC2 mutations, Thus, ZIC2 mutation was the apparent cause of HPE in 3-4% of cases. Seven mutations were frameshifts that were predicted to result in loss of function, further supporting the idea that ZIC2 haploinsufficiency can result in HPE, One mutation, an alanine tract expansion which is caused by the expansion of an imperfect trinucleotide repeat, occurred in seven patients from six different families. In three of those families, the father was found to be apparently mosaic for the mutation, We hypothesize that this mutation can arise through errors in somatic recombination, an extremely unusual mutation mechanism. In addition, one mutation resulted in a single amino acid change and one mutation was an in-frame deletion of 12 amino acids, The central nervous system malformations seen in patients with ZIC2 mutations ranged from alobar HPE (most common) to middle interhemispheric fusion defect tone case). Although severe facial anomalies are common in HPE, all of the patients with ZIC2 mutations had relatively normal faces, suggesting that ZIC2 mutations represent a large proportion of HPE cases without facial malformation.