Smith Claire E L, Murillo Gina, Brookes Steven J, Poulter James A, Silva Sandra, Kirkham Jennifer, Inglehearn Chris F, Mighell Alan J
Leeds Institute of Biomedical and Clinical Sciences, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
Department of Oral Biology, St James's University Hospital, University of Leeds, Leeds LS9 7TF, UK.
Hum Mol Genet. 2016 Aug 15;25(16):3578-3587. doi: 10.1093/hmg/ddw203. Epub 2016 Jul 12.
Amelogenesis imperfecta (AI) is a heterogeneous group of genetic conditions that result in defective dental enamel formation. Amelotin (AMTN) is a secreted protein thought to act as a promoter of matrix mineralization in the final stage of enamel development, and is strongly expressed, almost exclusively, in maturation stage ameloblasts. Amtn overexpression and Amtn knockout mouse models have defective enamel with no other associated phenotypes, highlighting AMTN as an excellent candidate gene for human AI. However, no AMTN mutations have yet been associated with human AI. Using whole exome sequencing, we identified an 8,678 bp heterozygous genomic deletion encompassing exons 3-6 of AMTN in a Costa Rican family segregating dominant hypomineralised AI. The deletion corresponds to an in-frame deletion of 92 amino acids, shortening the protein from 209 to 117 residues. Exfoliated primary teeth from an affected family member had enamel that was of a lower mineral density compared to control enamel and exhibited structural defects at least some of which appeared to be associated with organic material as evidenced using elemental analysis. This study demonstrates for the first time that AMTN mutations cause non-syndromic human AI and explores the human phenotype, comparing it with that of mice with disrupted Amtn function.
釉质发育不全（AI）是一组异质性的遗传疾病，会导致牙釉质形成缺陷。釉成熟蛋白（AMTN）是一种分泌蛋白，被认为在釉质发育的最后阶段作为基质矿化的促进因子，并且几乎仅在成熟阶段的成釉细胞中强烈表达。AMTN过表达和AMTN基因敲除小鼠模型具有牙釉质缺陷，且无其他相关表型，这突出了AMTN作为人类AI的一个优秀候选基因。然而，尚未发现AMTN突变与人类AI相关。我们使用全外显子组测序，在一个患有显性低矿化AI的哥斯达黎加家族中，鉴定出一个8678 bp的杂合基因组缺失，该缺失涵盖AMTN的外显子3至6。该缺失对应于92个氨基酸的框内缺失，使蛋白质从209个残基缩短至117个残基。与对照牙釉质相比，一名受影响家庭成员脱落的乳牙牙釉质矿密度较低，并且表现出结构缺陷，使用元素分析证明至少其中一些缺陷似乎与有机物质有关。这项研究首次证明AMTN突变会导致非综合征性人类AI，并探索了人类表型，并将其与Amtn功能 disrupted的小鼠的表型进行了比较。
