Novel genetic linkage of rat Sp6 mutation to Amelogenesis imperfecta.
Novel genetic linkage of rat Sp6 mutation to Amelogenesis imperfecta.
复制标题
DOI：
10.1186/1750-1172-7-34
复制
发表时间：
2012-06-07
影响因子：
3.7
通讯作者：
Noma T
中科院分区：
文献类型：
--
作者：
Muto T;Miyoshi K;Horiguchi T;Hagita H;Noma T
牙釉质发育异常是一种遗传性疾病，其特征是牙釉质的异常形成。虽然已经报道了几个负责AI的基因，但迄今为止尚未确定人类AI的所有致病基因。AMI大鼠是一种常染色体隐性遗传突变体，具有发育不良的AI，它是从一群易卒中的自发性高血压大鼠品系中分离出来的，但致病基因尚未阐明。通过遗传学筛选，我们确定了AMI常染色体隐性遗传AI的致病基因，并分析了其在釉质发生中的作用。迄今为止，使用第6天AMI大鼠磨牙的总RNA鉴定的可能的AI候选基因的cDNA测序在特异性蛋白6（Sp 6）中鉴定了一种新的负责突变。对AMI患者Sp 6基因与AI表型进行遗传连锁分析。为了了解SP 6在AI中的作用，我们在AMI中产生了携带Sp 6转基因的转基因大鼠（Ami/Ami + Tg）。分别使用对照大鼠、AMI和Ami/Ami + Tg上颌骨切牙的薄切片进行组织学分析。我们发现Sp 6基因的2个碱基插入突变与AMI大鼠AI表型之间存在新的遗传联系。突变位点位于SP 6的编码区，导致SP 6的第三锌指结构域发生移码突变，缺失11个氨基酸残基和一个终止密码子。转染研究表明，突变蛋白可以翻译和定位在细胞核中的野生型SP 6蛋白相同的方式。当我们将CMV启动子驱动的野生型Sp 6转基因导入AMI大鼠时，SP 6蛋白在成釉细胞的成熟期异位表达，与延长的成熟期和缩短的减少期相关，而没有任何其他表型变化。我们建议增加Sp 6突变作为常染色体隐性遗传AI患者的一个新的分子诊断标准。我们的研究结果扩展了常染色体隐性遗传性禽流感的遗传病因谱，并为禽流感的分子诊断分类提供了线索。此外，SP 6的时空表达的严格调节可能在完成釉质形成中具有关键作用。
Amelogenesis imperfecta (AI) is an inherited disorder characterized by abnormal formation of tooth enamel. Although several genes responsible for AI have been reported, not all causative genes for human AI have been identified to date. AMI rat has been reported as an autosomal recessive mutant with hypoplastic AI isolated from a colony of stroke-prone spontaneously hypertensive rat strain, but the causative gene has not yet been clarified. Through a genetic screen, we identified the causative gene of autosomal recessive AI in AMI and analyzed its role in amelogenesis. cDNA sequencing of possible AI-candidate genes so far identified using total RNA of day 6 AMI rat molars identified a novel responsible mutation in specificity protein 6 (Sp6). Genetic linkage analysis was performed between Sp6 and AI phenotype in AMI. To understand a role of SP6 in AI, we generated the transgenic rats harboring Sp6 transgene in AMI (Ami/Ami + Tg). Histological analyses were performed using the thin sections of control rats, AMI, and Ami/Ami + Tg incisors in maxillae, respectively. We found the novel genetic linkage between a 2-bp insertional mutation of Sp6 gene and the AI phenotype in AMI rats. The position of mutation was located in the coding region of Sp6, which caused frameshift mutation and disruption of the third zinc finger domain of SP6 with 11 cryptic amino acid residues and a stop codon. Transfection studies showed that the mutant protein can be translated and localized in the nucleus in the same manner as the wild-type SP6 protein. When we introduced the CMV promoter-driven wild-type Sp6 transgene into AMI rats, the SP6 protein was ectopically expressed in the maturation stage of ameloblasts associated with the extended maturation stage and the shortened reduced stage without any other phenotypical changes. We propose the addition of Sp6 mutation as a new molecular diagnostic criterion for the autosomal recessive AI patients. Our findings expand the spectrum of genetic causes of autosomal recessive AI and sheds light on the molecular diagnosis for the classification of AI. Furthermore, tight regulation of the temporospatial expression of SP6 may have critical roles in completing amelogenesis.
登录
查看更多内容
影响因子：
5
作者：
Hyun, H. -K.;Lee, S. -K.;Kim, J. -W.
通讯作者：
Kim, J. -W.
影响因子：
7.6
作者：
Kim, JW;Simmer, JP;Hu, JCC
通讯作者：
Hu, JCC
影响因子：
3
作者：
Collier, PM;Sauk, JJ;Gibson, CW
通讯作者：
Gibson, CW
影响因子：
3
作者：
Hart, PS;Aldred, MJ;Wright, JT
通讯作者：
Wright, JT
影响因子：
1.9
作者：
Kim, Jung-Wook;Simmer, James P.;Hu, Jan C. -C.
通讯作者：
Hu, Jan C. -C.