Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia
Hypomorphic Mutations in TONSL Cause SPONASTRIME Dysplasia
复制标题
DOI：
10.1016/j.ajhg.2019.01.009
复制
发表时间：
2019-03-07
影响因子：
9.8
通讯作者：
Cho, Tae-Joon
中科院分区：
文献类型：
--
作者：
Chang, Hae Ryung;Cho, Sung Yoon;Cho, Tae-Joon
SPONASTRIME发育不良是一种罕见的隐性骨骼发育不良，其特征是身材矮小，面部畸形，脊柱和长骨干部的x线表现异常。SPONASTRIME发育不良的致病基因改变尚未确定。利用全外显子组测序（WES），我们在13例SPONASTRIME不典型增生患者中的10例中发现了双等位基因TONSL突变。TONSL是一种与DNA复制和修复因子相互作用的多结构域支架蛋白，在抵抗复制应激和维持基因组完整性方面起着关键作用。我们在这里表明，来自受影响个体的真皮成纤维细胞的细胞缺陷被野生型TONSL的表达所补充。此外，基于体外细胞和计算机对TONSL结构的分析支持了这些TONSL变异的致病性。有趣的是，敲入（KI） Tonsl小鼠模型导致胚胎致死，这暗示了Tonsl的生理重要性。总之，这些发现表明，导致TONSL功能降低的遗传变异导致了SPONASTRIME发育不良，并突出了TONSL在胚胎发育和出生后生长中的重要性。
SPONASTRIME dysplasia is a rare, recessive skeletal dysplasia characterized by short stature, facial dysmorphism, and aberrant radiographic findings of the spine and long bone metaphysis. No causative genetic alterations for SPONASTRIME dysplasia have yet been determined. Using whole-exome sequencing (WES), we identified bi-allelic TONSL mutations in 10 of 13 individuals with SPONASTRIME dysplasia. TONSL is a multi-domain scaffold protein that interacts with DNA replication and repair factors and which plays critical roles in resistance to replication stress and the maintenance of genome integrity. We show here that cellular defects in dermal fibroblasts from affected individuals are complemented by the expression of wild-type TONSL. In addition, in vitro cell-based as-says and in silico analyses of TONSL structure support the pathogenicity of those TONSL variants. Intriguingly, a knock-in (KI) Tonsl mouse model leads to embryonic lethality, implying the physiological importance of TONSL. Overall, these findings indicate that genetic variants resulting in reduced function of TONSL cause SPONASTRIME dysplasia and highlight the importance of TONSL in embryonic development and postnatal growth.