Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia
Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia
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DOI：
10.1172/jci69746
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发表时间：
2013-08-01
影响因子：
15.9
通讯作者：
Zeng, Li
中科院分区：
文献类型：
--
作者：
Cairns, Dana M.;Pignolo, Robert J.;Zeng, Li
进行性骨异型增生（POH）是一种罕见的异位骨化（HO）发育障碍，由GNAS基因的父系等位基因中的杂合失活生殖系突变引起。有趣的是，POH病变具有令人困惑的马赛克分布。通过临床、影像学和摄影记录，我们发现12名受试者中的大多数对一侧或另一侧有病变偏倚，甚至表现出单侧性。最引人注目的是，所有人都有HO病变的真皮肌层分布。我们假设体细胞起源的祖细胞中的体细胞突变可能作用于种系单倍不足的背景，导致GNAS位点的杂合性丢失，并导致POH病变的单侧分布。利用鸡系统，我们研究了我们的假设，通过模拟GNAS表达的杂合性丢失，使用显性阴性GNAS，引入到鸡体节的一个子集，产生真皮和肌肉的祖细胞。我们观察到快速异位软骨和骨诱导在轴向和横向位置在一个单边的分布对应于注射体节，这表明，在一个目标群体的祖细胞阻断GNAS活动可以导致马赛克异位骨化联想到POH。
Progressive osseous heteroplasia (POH) is a rare developmental disorder of heterotopic ossification (HO) caused by heterozygous inactivating germline mutations in the paternal allele of the GNAS gene. Interestingly, POH lesions have a bewildering mosaic distribution. Using clinical, radiographic, and photographic documentation, we found that most of the 12 individuals studied had a lesional bias toward one side or the other, even showing exclusive sidedness. Most strikingly, all had a dermomyotomal distribution of HO lesions. We hypothesized that somatic mutations in a progenitor cell of somitic origin may act on a background of germline haploinsufficiency to cause loss of heterozygosity at the GNAS locus and lead to the unilateral distribution of POH lesions. Taking advantage of the chick system, we examined our hypothesis by mimicking loss of heterozygosity of GNAS expression using dominant-negative GNAS that was introduced into a subset of chick somites, the progenitors that give rise to dermis and muscle. We observed rapid ectopic cartilage and bone induction at the axial and lateral positions in a unilateral distribution corresponding to the injected somites, which suggests that blocking GNAS activity in a targeted population of progenitor cells can lead to mosaic ectopic ossification reminiscent of that seen in POH.