Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR
Oculofaciocardiodental and Lenz microphthalmia syndromes result from distinct classes of mutations in BCOR
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DOI：
10.1038/ng1321
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发表时间：
2004-04-01
期刊：
影响因子：
30.8
通讯作者：
Biesecker, LG
中科院分区：
文献类型：
--
作者：
Ng, D;Thakker, N;Biesecker, LG
伦茨小眼症以X连锁隐性模式遗传，包括小眼症、智力迟钝、骨骼和其他异常。与该综合征相关的两个位点，MAA（小眼畸形伴相关异常）和MAA 2，分别位于Xq27-q28（参考文献1）。1，2）和Xp11.4-p21.2（参考文献3）。我们在以前用于鉴定MAA 2基因座3的伦茨综合征家族中的受影响男性的BCOR（编码BCL-6相互作用辅阻遏物，BCOR 4）中鉴定了一个替换，nt 254 C--> T; P85 L。眼面心齿综合征（OFCD; OMIM 300166）以X连锁显性模式遗传，推测为男性致死性，包括小眼球、先天性白内障、神经根肥大以及心脏和手指畸形。鉴于其表型重叠，我们提出OFCD和MAA 2相关的伦茨小眼症是等位基因，我们发现不同的移码，缺失和无义突变的BCOR在7个家庭与OFCD影响。与野生型BCOR一样，BCOR P85 L和BCOR的OVCD突变形式可以与BCL-6相互作用并有效抑制转录。这表明这些综合征可能是由于BCOR替代功能的缺陷，例如与BCL-6以外的转录伙伴的相互作用。我们克隆了BCOR的斑马鱼（Danio rerio）直系同源物，发现敲除该直系同源物会引起与人类综合征一致的眼睛，骨骼和中枢神经系统的发育扰动，证实BCOR是早期胚胎发生过程中的关键转录调节因子。
Lenz microphthalmia is inherited in an X-linked recessive pattern and comprises microphthalmia, mental retardation, and skeletal and other anomalies. Two loci associated with this syndrome, MAA ( microphthalmia with associated anomalies) and MAA2, are situated respectively at Xq27-q28 (refs. 1,2) and Xp11.4-p21.2 (ref. 3). We identified a substitution, nt 254C --> T; P85L, in BCOR (encoding BCL-6-interacting corepressor, BCOR 4) in affected males from the family with Lenz syndrome previously used to identify the MAA2 locus 3. Oculofaciocardiodental syndrome (OFCD; OMIM 300166) is inherited in an X-linked dominant pattern with presumed male lethality and comprises microphthalmia, congenital cataracts, radiculomegaly, and cardiac and digital abnormalities. Given their phenotypic overlap, we proposed that OFCD and MAA2 - associated Lenz microphthalmia were allelic, and we found different frameshift, deletion and nonsense mutations in BCOR in seven families affected with OFCD. Like wild-type BCOR, BCOR P85L and an OFCD-mutant form of BCOR can interact with BCL-6 and efficiently repress transcription. This indicates that these syndromes are likely to result from defects in alternative functions of BCOR, such as interactions with transcriptional partners other than BCL-6. We cloned the zebrafish (Danio rerio) ortholog of BCOR and found that knock-down of this ortholog caused developmental perturbations of the eye, skeleton and central nervous system consistent with the human syndromes, confirming that BCOR is a key transcriptional regulator during early embryogenesis.