A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families
A novel missense mutation in MSX1 underlies autosomal recessive oligodontia with associated dental anomalies in Pakistani families
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DOI：
10.1007/s10038-006-0037-x
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发表时间：
2006-10-01
影响因子：
3.5
通讯作者：
Ahmad, Wasim
中科院分区：
文献类型：
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作者：
Chishti, Muhammad S.;Muhammad, Dost;Ahmad, Wasim
牙齿发育不全是人类牙齿发育最常见的异常。在大多数单独或合并其他畸形的家族性缺牙病例中，遗传方式为常染色体显性遗传。在本研究中，我们鉴定了两个有远亲血缘关系的巴基斯坦家庭，他们患有常染色体隐性形式的缺牙，并伴有牙齿异常。此例中的基因座已定位在染色体4p16.1-p16.3上。标记D4S2925和D4S2285的最大两点LOD得分为2.85(theta=0.0)。在相同的标记上，最大多点LOD评分超过4分。在受影响个体中观察到的重组事件将疾病基因定位在标记D4S412和D4S2935之间，跨越染色体4p16.1-p16.3上9.24 cM的区域。对候选基因Msx1的序列分析发现了一个新的隐性错义突变，导致位于Msx1同源结构域的丙氨酸替换为苏氨酸(p.A219T)，该突变对DNA结合和蛋白质相互作用具有重要意义。该突变名为p.A219T，是在Msx1中发现的第一个隐性突变。
Tooth agenesis constitutes the most common anomaly of dental development in humans. In the majority of familial cases of hypodontia alone or in association with other anomalies, the mode of inheritance is autosomal dominant. In the present study, we have identified two distantly related consanguineous Pakistani kindreds with an autosomal recessive form of oligodontia with associated dental anomalies. Locus in this case has been mapped on chromosome 4p16.1-p16.3. The maximum two-point LOD score of 2.85 (theta=0.0) was obtained at markers D4S2925 and D4S2285. A maximum multipoint LOD score exceeding 4 was obtained at the same markers. Recombination events observed in affected individuals localized the disease locus between markers D4S412 and D4S2935, spanning a 9.24-cM region on chromosome 4p16.1-p16.3. Sequence analysis of candidate gene MSX1 revealed a novel recessive missense mutation resulting in substitution of alanine to threonine amino acid (p. A219T), located in the MSX1 homeodomain, which is important for DNA binding and protein-protein interaction. The mutation, p. A219T, is the first recessive mutation identified in MSX1.