BMP4 mutations in tooth agenesis and low bone mass
BMP4 mutations in tooth agenesis and low bone mass
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BMP4 突变导致牙齿发育不全和低骨量
DOI：
10.1016/j.archoralbio.2019.05.012
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发表时间：
2019-07-01
影响因子：
3
通讯作者：
Feng, Hailan
中科院分区：
文献类型：
--
作者：
Yu, Miao;Wang, Hao;Feng, Hailan
目的：通过利用全外显子组测序 (WES) 和靶向桑格测序，在 120 名孤立的 TA 患者中识别牙齿发育不全 (TA) 的罕见遗传原因。设计：通过 WES 在 6 名不相关的 TA 患者中鉴定出编码骨形态发生蛋白 4 (BMP4) 的基因中的一个有害突变。之后，使用桑格测序对 114 名 TA 患者的 BMP4 编码外显子进行了检查。双能 X 射线吸收测定法 (DEXA) 用于测量携带 BMP4 突变的患者的骨矿物质密度。最后，对两个 BMP4 突变体进行了初步功能研究。结果：我们在 120 名 TA 先证者中检测到 3 个新的错义突变（c.58 G > A：p.Gly2OSer、c.326 G > T：p.Arg109Leu 和 c.614 T > C：p.Va1205A1a）和 1 个报道的 BMP4 基因突变。先前报道的 BMP4 突变 (c.751C > T: p.His251Tyr) 与尿道和眼睛异常相关。通过扩展谱系，我们确定牙齿表型具有常染色体显性遗传模式，因为携带 BMP4 突变的个体表现出不同类型的牙齿异常。有趣的是，我们观察到携带 BMP4 突变的患者表现出早发性骨质减少或骨质疏松症。进一步的体外功能测定表明，两种 BMP4 突变体导致 Smad 信号激活减少。因此，BMP4 的功能丧失可能导致本研究中出现的临床表型。结论：我们在 120 名 TA 患者中发现了 BMP4 基因的 4 个突变。据我们所知，这是第一项描述与 BMP4 突变相关的人类骨骼疾病的研究。
Objective: To identify an uncommon genetic cause of tooth agenesis (TA) by utilizing whole exome sequencing (WES) and targeted Sanger sequencing in a cohort of 120 patients with isolated TA.Design: One deleterious mutation in the gene encoding bone morphogenetic protein 4 (BMP4) was identified in 6 unrelated patients with TA by WES. After that, the coding exons of BMP4 were examined in 114 TA patients using Sanger sequencing. Dual-energy X-ray absorptiometry (DEXA) was used to measure the bone mineral density of patients who carried a BMP4 mutation. Finally, preliminary functional studies of two BMP4 mutants were performed.Results: We detected 3 novel missense mutations (c.58 G > A: p.Gly2OSer, c.326 G > T: p.Arg109Leu and c.614 T > C: p.Va1205A1a) and 1 reported mutation in the BMP4 gene among 120 TA probands. The previously reported BMP4 mutation (c.751C > T: p.His251Tyr) was associated with urethra and eye anomalies. By extending the pedigrees, we determined that the tooth phenotypes had an autosomal dominant inheritance pattern, as individuals carrying a BMP4 mutation exhibit different types of dental anomalies. Interestingly, we observed that patients harboring a BMP4 mutation manifested early onset osteopenia or osteoporosis. Further in vitro functional assays demonstrated that two BMP4 mutants resulted in a decreased activation of Smad signaling. Therefore, a loss-of-function in BMP4 may contribute to the clinical phenotypes seen in this study.Conclusions: We identified 4 mutations in the BMP4 gene in 120 TA patients. To our knowledge, this is the first study to describe human skeletal diseases associated with BMP4 mutations.