A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities.
A Fourth KLK4 Mutation Is Associated with Enamel Hypomineralisation and Structural Abnormalities.
复制标题
DOI：
10.3389/fphys.2017.00333
复制
发表时间：
2017
影响因子：
4
通讯作者：
Brookes SJ
中科院分区：
文献类型：
--
作者：
Smith CEL;Kirkham J;Day PF;Soldani F;McDerra EJ;Poulter JA;Inglehearn CF;Mighell AJ;Brookes SJ
“釉质发生障碍”（AI）描述了一组导致牙釉质形成缺陷的遗传条件。已知许多基因的突变导致AI，包括编码丝氨酸蛋白酶的基因，激肽释放酶相关肽酶4（KLK 4），其在釉质形成的成熟阶段期间表达。在这项研究中，我们报告了在常染色体隐性遗传性发育不良型AI中发现的第四个KLK 4突变，c.632delT，p.（L211Rfs*37）（NM_004917.4，NP_004908.4）。这种纯合变体在五个巴基斯坦AI家族中被鉴定，并且预测会导致具有逃避无义介导的衰变的提前终止密码子的转录本。然而，蛋白质可能会错误折叠，因为六个二硫键中的三个会被破坏，并且可能因此而降解或无功能。乳牙从一个受影响的个体获得。采用高分辨率计算机X射线断层扫描（CT）、扫描电子显微镜（SEM）、能量色散X射线光谱（EDX）和显微硬度测试（MH）对釉质表型进行表征。与匹配的对照牙釉质相比，受影响个体的牙釉质（称为KLK 4牙釉质）矿化不足。此外，与KLK 4外釉质相比，KLK 4内釉质矿化不足。SEM显示KLK 4内釉质和外釉质之间的清晰结构分界，尽管釉质结构总体上与对照组织相似。EDX显示KLK 4内釉中钙、磷含量低于对照内釉和KLK 4外釉，氮含量高于对照外釉。MH测试显示KLK 4内釉质比KLK 4外釉质明显更软（p < 0.001）。然而，对照内釉质的硬度与对照外釉质的硬度无显著差异。总体而言，这些研究结果表明，KLK 4 c.632delT突变可能是巴基斯坦人群中常染色体隐性AI的常见原因。获得的表型数据反映了Klk 4 −/−小鼠的发现，并表明KLK 4是内釉质层硬化和矿化所必需的，但对外釉质层硬化和矿化不太重要。
“Amelogenesis imperfecta” (AI) describes a group of genetic conditions that result in defects in tooth enamel formation. Mutations in many genes are known to cause AI, including the gene encoding the serine protease, kallikrein related peptidase 4 (KLK4), expressed during the maturation stage of amelogenesis. In this study we report the fourth KLK4 mutation to be identified in autosomal recessively-inherited hypomaturation type AI, c.632delT, p.(L211Rfs*37) (NM_004917.4, NP_004908.4). This homozygous variant was identified in five Pakistani AI families and is predicted to result in a transcript with a premature stop codon that escapes nonsense mediated decay. However, the protein may misfold, as three of six disulphide bonds would be disrupted, and may be degraded or non-functional as a result. Primary teeth were obtained from one affected individual. The enamel phenotype was characterized using high-resolution computerized X-ray tomography (CT), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDX), and microhardness testing (MH). Enamel from the affected individual (referred to as KLK4 enamel) was hypomineralised in comparison with matched control enamel. Furthermore, KLK4 inner enamel was hypomineralised compared with KLK4 outer enamel. SEM showed a clear structural demarcation between KLK4 inner and outer enamel, although enamel structure was similar to control tissue overall. EDX showed that KLK4 inner enamel contained less calcium and phosphorus and more nitrogen than control inner enamel and KLK4 outer enamel. MH testing showed that KLK4 inner enamel was significantly softer than KLK4 outer enamel (p < 0.001). However, the hardness of control inner enamel was not significantly different to that of control outer enamel. Overall, these findings suggest that the KLK4 c.632delT mutation may be a common cause of autosomal recessive AI in the Pakistani population. The phenotype data obtained mirror findings in the Klk4−/− mouse and suggest that KLK4 is required for the hardening and mineralization of the inner enamel layer but is less essential for hardening and mineralization of the outer enamel layer.