Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype
Nine Novel PAX9 Mutations and a Distinct Tooth Agenesis Genotype-Phenotype
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九种新的 PAX9 突变和独特的牙齿发育不全基因型-表型
DOI：
10.1177/0022034517729322
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发表时间：
2018-02-01
影响因子：
7.6
通讯作者：
Feng, H.
中科院分区：
文献类型：
--
作者：
Wong, S. -W.;Han, D.;Feng, H.
牙齿发育不全是影响功能和美观的最常见的发育异常之一。配对结构域转录因子 Pax9 对于牙齿和味蕾的模式形成和形态发生至关重要。已在牙齿发育不全患者中发现 PAX9 突变。尽管牙齿发育不全的遗传学取得了重大进展，但在完善 PAX9 与牙齿发育不全之间的基因型-表型相关性方面仍存在许多知识空白。在本研究中，我们完成了具有非综合征（NS）牙齿发育不全的多重中国家庭的遗传和表型特征。聚合酶链反应产物的直接测序揭示了 PAX9 基因中的 9 个新突变（c.140G>C、c.167T>A、c.332G>C、c.194C>A、c.271A>T、c.146delC、c.185_189dup、c.256_262dup 和 c.592delG）和 2 个已知杂合突变。 120 先证者。随后，谱系得到扩展，我们证实突变与牙齿发育不全表型共分离（无法进行 DNA 分析的家族除外）。在 1 个家族 (n = 6) 中，2 个人同时携带 PAX9 c.592delG 突变和 MSX1 基因中的杂合错义突变 (c.739C>T)。分离 PAX9 突变的家族的临床特征表明，所有受影响的个体都缺失下颌第二磨牙，并且他们的上颌中切牙最容易出现小牙。据记录，携带 PAX9 突变的个体苦味感知显着降低 (n = 3)。功能研究表明，PAX9 单倍体不足或 PAX9 蛋白功能丧失是牙齿发育不全的基础。
Tooth agenesis is one of the most common developmental anomalies affecting function and esthetics. The paired-domain transcription factor, Pax9, is critical for patterning and morphogenesis of tooth and taste buds. Mutations of PAX9 have been identified in patients with tooth agenesis. Despite significant progress in the genetics of tooth agenesis, many gaps in knowledge exist in refining the genotype-phenotype correlation between PAX9 and tooth agenesis. In the present study, we complete genetic and phenotypic characterization of multiplex Chinese families with nonsyndromic (NS) tooth agenesis. Direct sequencing of polymerase chain reaction products revealed 9 novel (c.140G>C, c.167T>A, c.332G>C, c.194C>A, c.271A>T, c.146delC, c.185_189dup, c.256_262dup, and c.592delG) and 2 known heterozygous mutations in the PAX9 gene among 120 probands. Subsequently, pedigrees were extended, and we confirmed that the mutations co-segregated with the tooth agenesis phenotype (with exception of families in which DNA analysis was not available). In 1 family (n = 6), 2 individuals harbored both the PAX9 c.592delG mutation and a heterozygous missense mutation (c.739C>T) in the MSX1 gene. Clinical characterization of families segregating a PAX9 mutation reveal that all affected individuals were missing the mandibular second molar and their maxillary central incisors are most susceptible to microdontia. A significant reduction of bitter taste perception was documented in individuals harboring PAX9 mutations (n = 3). Functional studies revealed that PAX9 haploinsufficiency or a loss of function of the PAX9 protein underlies tooth agenesis.