Novel PITX2 mutations identified in Axenfeld-Rieger syndrome and the pattern of PITX2-related tooth agenesis
Novel PITX2 mutations identified in Axenfeld-Rieger syndrome and the pattern of PITX2-related tooth agenesis
复制标题
Axenfeld–Rieger 综合征中发现的新 PITX2 突变以及 PITX2– 相关牙齿发育不全的模式
DOI：
10.1111/odi.13196
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发表时间：
2019-11-01
期刊：
影响因子：
3.8
通讯作者：
Feng, Hailan
中科院分区：
文献类型：
--
作者：
Fan, Zhuangzhuang;Sun, Shichen;Feng, Hailan
目的研究Axenet-Rieger综合征（ARS）患者的PITX 2基因突变情况及PITX 2基因相关的牙齿发育不全模式。方法采用全外显子测序（WES）和拷贝数变异（CNV）芯片技术对4例ARS先证者进行突变筛查。在桑格测序和定量聚合酶链反应（qPCR）验证后，采用二级结构预测和双荧光素酶测定来研究功能影响。从我们的数据库和文献中检索到18例有明确牙科记录的PITX 2突变患者，并分析PITX 2相关牙齿发育不全的模式。结果发现了一个新的4 q25（GRCh 37/hg 19 chr 4：111，320，052-111，754，236）的片段性缺失，包括PITX 2和三个新的PITX 2突变c.148C > T，c.257G > A和c.630insCG。初步的功能研究表明，突变体PITX 2对DLX 2启动子的反式激活能力受到损害。上颌牙发育不全率（57.94%）明显高于下颌牙（44.05%）。缺牙以上颌侧切牙（83.33%）和上颌第二前磨牙（69.44%）最多。下颌第二磨牙和下颌第一磨牙缺失率最低，分别为19.44%和8.33%。结论我们发现了一个新的4 q25微缺失，包括PITX 2和三个新的PITX 2突变，并对PITX 2相关的牙齿发育不全模式进行了统计分析。
Objectives To investigate the mutations in patients with Axenfeld-Rieger syndrome (ARS) and the pattern of PITX2-related tooth agenesis. Methods Whole-exome sequencing (WES) and copy number variation (CNV) array were used to screen the mutations in four ARS probands. After Sanger sequencing and quantitative polymerase chain reaction (qPCR) validation, secondary structure prediction and dual-luciferase assay were employed to investigate the functional impact. Eighteen PITX2-mutated patients with definite dental records were retrieved from our database and literatures, and the pattern of PITX2-related tooth agenesis was analyzed. Results A novel de novo segmental deletion of chromosome 4q25 (GRCh37/hg19 chr4:111, 320, 052-111, 754, 236) encompassing PITX2 and three novel PITX2 mutations c.148C > T, c.257G > A, and c.630insCG were identified. Preliminary functional studies indicated the transactivation capacity of mutant PITX2 on Distal-less homeobox 2 (DLX2) promoter was compromised. The maxillary teeth showed significantly higher rate of agenesis (57.94%) than the mandibular teeth (44.05%). The most often missing teeth were upper lateral incisors (83.33%) and upper second premolars (69.44%). Teeth with the least agenesis rate were the lower second molars (19.44%) and lower first molars (8.33%). Conclusions We identified a novel 4q25 microdeletion including PITX2 and three novel PITX2 mutations, and statistically analyzed the PITX2-related tooth agenesis pattern.