A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome
A microduplication of the long range SHH limb regulator (ZRS) is associated with triphalangeal thumb-polysyndactyly syndrome
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DOI：
10.1136/jmg.2007.055699
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发表时间：
2008-06-01
影响因子：
4
通讯作者：
Lehmann, K.
中科院分区：
文献类型：
--
作者：
Klopocki, E.;Ott, C-E;Lehmann, K.
背景：Sonic Hedgehog(SHH)在确定四肢发育中的前后轴方面起着重要作用。位于sonic hedgehog基因(SHH)上游的一个高度保守的非编码序列(Sonic hedgehog gene，SHH)约为1Mb，是SHH在肢芽中表达的长距离调控因子。这个名为ZRs的非编码调节区内的点突变导致Shh在肢芽的前缘异位表达，如小鼠所示，并导致人类三指拇指和多并指(TPT-PS)表型。尽管这种关联已经建立，但其分子机制仍不清楚。方法和结果：我们调查了一个具有可变TPT-PS的大型家系。SHH肢体调节序列中的单核苷酸交换被排除，但位点特异的微卫星标记分析证实了与该区域的连锁。随后，使用亚百万碱基全人类基因组平铺路径细菌人工染色体(BAC)阵列进行阵列比较基因组杂交(阵列CGH)，发现在受影响的个体中存在7q36.3的微复制。通过实时定量聚合酶链式反应(QPCR)和直接测序鉴定出包含ZRs的588,819个碱基的重复区域。结论：7q36.3中的一个新的微重复导致了类似于肢体特异性SHH调节元件ZRs的单核苷酸改变引起的TPT-PS表型。复制可以被添加到越来越多的导致远程转录控制异常的机制清单中。
Background: Sonic hedgehog (SHH) plays an important role in defining the anterior-posterior axis in the developing limbs. A highly conserved non-coding sequence about similar to 1 Mb upstream from the sonic hedgehog gene (SHH) was shown to be a long range regulator for SHH expression in the limb bud. Point mutations within this non-coding regulatory region designated ZRS lead to ectopic expression of Shh in the anterior margin of the limb bud, as shown in mice, and cause the human triphalangeal thumb and polysyndactyly (TPT-PS) phenotype. Even though this association is well established, its molecular mechanism remains unclear.Methods and results: We investigated a large pedigree with variable TPT-PS. A single nucleotide exchange within the SHH limb regulator sequence was excluded, but locus specific microsatellite marker analyses confirmed a linkage to this region. Subsequently, array comparative genomic hybridisation (array CGH) was carried out using a submegabase whole human genome tiling path bacterial artificial chromosome (BAC) array revealing a microduplication in 7q36.3 in affected individuals. A duplicated region of 588,819 bp comprising the ZRS was identified by quantitative real-time polymerase chain reaction (qPCR) and direct sequencing.Conclusion: A novel microduplication in 7q36.3 results in a similar TPT-PS phenotype as caused by single nucleotide alterations in the ZRS, the limb specific SHH regulatory element. Duplications can be added to the growing list of mechanisms that cause abnormalities of long range transcriptional control.