Department of Prosthodontics, Peking University School and Hospital of Stomatology, National Clinical Research Center for Oral Diseases, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, China.
Department of Internal Medicine, Sanford Medical School, University of South Dakota, Sioux Falls, SD, 57105, USA.
Arch Oral Biol. 2019 Jul;103:40-46. doi: 10.1016/j.archoralbio.2019.05.012. Epub 2019 May 15.
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.
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.
We detected 3 novel missense mutations (c.58 G > A: p.Gly20Ser, c.326 G > T: p.Arg109Leu and c.614 T > C: p.Val205Ala) 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.
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.
通过对 120 例孤立性牙齿缺失（TA）患者进行全外显子组测序（WES）和靶向 Sanger 测序，确定 TA 的罕见遗传病因。
通过 WES 在 6 例 TA 患者中发现了一个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 Sanger 测序对 114 例 TA 患者的 BMP4 编码外显子进行了检测。对携带 BMP4 突变的患者进行了双能 X 线吸收法（DEXA）骨密度测量。最后，对两个 BMP4 突变体进行了初步的功能研究。
我们在 120 例 TA 先证者中检测到 3 个新的错义突变（c.58G>A：p.Gly20Ser，c.326G>T：p.Arg109Leu 和 c.614T>C：p.Val205Ala）和 1 个已报道的 BMP4 基因中的突变（c.751C>T：p.His251Tyr）。之前报道的 BMP4 突变（c.751C>T：p.His251Tyr）与尿道和眼部异常有关。通过扩展家系，我们确定牙齿表型呈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疏松症或骨质疏松症。进一步的体外功能测定表明，两个 BMP4 突变体导致 Smad 信号转导的活性降低。因此，BMP4 的功能丧失可能导致本研究中所见的临床表型。
我们在 120 例 TA 患者中发现了 BMP4 基因的 4 个突变。据我们所知，这是第一个描述与 BMP4 突变相关的人类骨骼疾病的研究。
