Enamelin (Enam) is essential for amelogenesis:: ENU-induced mouse mutants as models for different clinical subtypes of human amelogenesis imperfecta (Al)
Enamelin (Enam) is essential for amelogenesis:: ENU-induced mouse mutants as models for different clinical subtypes of human amelogenesis imperfecta (Al)
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DOI：
10.1093/hmg/ddi054
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发表时间：
2005-03-01
影响因子：
3.5
通讯作者：
Shiroishi, T
中科院分区：
文献类型：
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作者：
Masuya, H;Shimizu, K;Shiroishi, T
Amelogenesoes Interfecta（AI）是一组牙齿牙釉质形成的常见缺陷，该缺陷表现出标记的遗传和临床异质性。这种异质性的遗传基础仍然很少了解。搪瓷蛋白是一种形式的AI（AIH2），是一种细胞外基质蛋白，是搪瓷的成分之一。我们分离了三个ENU诱导的显性小鼠突变，即M100395，M100514和M100521，它们在受影响个体的切牙和磨牙中引起了AI样表型。连锁分析将三个突变中的每个突变映射到染色体5的区域，其中包含编码搪瓷（eNAM）和氨基糖蛋白（AMBN）的基因。序列分析表明，每个突变都是enam中的单基替代。 M100395（ENAM（RGSC395））和M100514（ENAM（RGSC514））是推定的错义突变，分别在翻译蛋白的55和57位置对i和e进行了s替换。 ENAM（RGSC395）和ENAM（RGSC514）杂合子表现出严重的牙釉质表面破裂，牙釉质表面类似于局部发育不全AI。 M100521突变（ENAM（RGSC521））是内含子4中剪接供体位点取代的t。该突变导致更新的移率，从而引起了早产停止密码子。 eNAM（RGSC521）突变等位基因的转录被降解，表明ENAM（RGSC521）是功能丧失的突变。 ENAM（RGSC521）杂合子在切牙中显示出不饱和类型的AI表型，这可能是由于eNAM的单倍不足所致。 eNAM（RGSC521）纯合子在切牙和磨牙上显示牙釉质完全丧失。因此，我们在这里报告说，eNAM基因对于没有变性至关重要，并且在ENAM上具有不同点突变的小鼠可能会提供良好的动物模型来研究AI的不同临床亚型。
Amelogenesis imperfecta (AI) is a group of commonly inherited defects of dental enamel formation, which exhibits marked genetic and clinical heterogeneity. The genetic basis of this heterogeneity is still poorly understood. Enamelin, the affected gene product in one form of AI (AIH2), is an extracellular matrix protein that is one of the components of enamel. We isolated three ENU-induced dominant mouse mutations, M100395, M100514 and M100521, which caused AI-like phenotypes in the incisors and molars of the affected individuals. Linkage analyses mapped each of the three mutations to a region of chromosome 5 that contained the genes encoding enamelin (Enam) and ameloblastin (Ambn). Sequence analysis revealed that each mutation was a single-base substitution in Enam. M100395 (Enam(Rgsc395)) and M100514 (Enam(Rgsc514)) were putative missense mutations that caused S to I and E to G substitutions at positions 55 and 57 of the translated protein, respectively. Enam(Rgsc395) and Enam(Rgsc514) heterozygotes showed severe breakage of the enamel surface, a phenotype that resembled local hypoplastic AI. The M100521 mutation (Enam(Rgsc521)) was a T to A substitution at the splicing donor site in intron 4. This mutation resulted in a frameshift that gave rise to a premature stop codon. The transcript of the Enam(Rgsc521) mutant allele was degraded, indicating that Enam(Rgsc521) is a loss-of-function mutation. Enam(Rgsc521) heterozygotes showed a hypomaturation-type AI phenotype in the incisors, possibly due to haploinsufficiency of Enam. Enam(Rgsc521) homozygotes showed complete loss of enamel on the incisors and the molars. Thus, we report here that the Enam gene is essential for amelogenesis, and that mice with different point mutations at Enam may provide good animal models to study the different clinical subtypes of AI.