An aberrant splice acceptor site due to a novel intronic nucleotide substitution in MSX1 gene is the cause of congenital tooth agenesis in a Japanese family.
An aberrant splice acceptor site due to a novel intronic nucleotide substitution in MSX1 gene is the cause of congenital tooth agenesis in a Japanese family.
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DOI：
10.1371/journal.pone.0128227
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Tokita Y
中科院分区：
文献类型：
--
作者：
Tatematsu T;Kimura M;Nakashima M;Machida J;Yamaguchi S;Shibata A;Goto H;Nakayama A;Higashi Y;Miyachi H;Shimozato K;Matsumoto N;Tokita Y
先天性牙齿发育不全是由MSX 1、PAX 9、WNT 10A或AXIN 2基因突变引起的。在这里，我们报告了一个日本家庭与非综合征性牙齿发育不全造成的一个新的核苷酸取代之间的外显子1和2的MSX 1基因的内含子区域。由于突变位于外显子2前9 bp（c.452- 9 G>A），我们推测核苷酸替换将产生异常剪接位点。使用永生化患者血细胞的cDNA分析，我们证实，一个额外的7-核苷酸序列插入在外显子1和2之间的剪接连接（c.451_452insCCCTCAG）。随后的移码产生同源域截短的MSX 1（p.R151fsX20）。然后我们研究了截短的MSX 1蛋白在COS细胞中的亚细胞定位，并观察到与野生型蛋白相比，它具有全细胞分布而不是核定位。该结果表明核定位信号的缺失，其定位于MSX 1同源结构域。这些结果表明，这种新的内含子核苷酸替换是该家族牙齿发育不全的原因。迄今为止，大多数MSX 1变异体分离出的牙齿发育不全患者涉及单一的氨基酸取代高度保守的同源结构域或缺失突变引起的移码或无义突变。我们在这里报告一个罕见的情况下，一个内含子突变的MSX 1基因负责人类牙齿发育不全。此外，缺失的牙齿模式略有不同，但显着影响同卵双胞胎对这个家庭，表观遗传或环境因素也影响患者的表型变异缺失的牙齿由MSX 1单倍型不足引起的非综合征性牙齿发育不全。
Congenital tooth agenesis is caused by mutations in the MSX1, PAX9, WNT10A, or AXIN2 genes. Here, we report a Japanese family with nonsyndromic tooth agenesis caused by a novel nucleotide substitution in the intronic region between exons 1 and 2 of the MSX1 gene. Because the mutation is located 9 bp before exon 2 (c.452-9G>A), we speculated that the nucleotide substitution would generate an abnormal splice site. Using cDNA analysis of an immortalized patient blood cell, we confirmed that an additional 7-nucleotide sequence was inserted at the splice junction between exons 1 and 2 (c.451_452insCCCTCAG). The consequent frameshift generated a homeodomain-truncated MSX1 (p.R151fsX20). We then studied the subcellular localization of truncated MSX1 protein in COS cells, and observed that it had a whole cell distribution more than a nuclear localization, compared to that of wild-type protein. This result suggests a deletion of the nuclear localization signal, which is mapped to the MSX1 homeodomain. These results indicate that this novel intronic nucleotide substitution is the cause of tooth agenesis in this family. To date, most MSX1 variants isolated from patients with tooth agenesis involve single amino acid substitutions in the highly conserved homeodomain or deletion mutants caused by frameshift or nonsense mutations. We here report a rare case of an intronic mutation of the MSX1 gene responsible for human tooth agenesis. In addition, the missing tooth patterns were slightly but significantly different between an affected monozygotic twin pair of this family, showing that epigenetic or environmental factors also affect the phenotypic variations of missing teeth among patients with nonsyndromic tooth agenesis caused by an MSX1 haploinsufficiency.
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