A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta
A novel FAM83H mutation in one Chinese family with autosomal-dominant hypocalcification amelogenesis imperfecta
复制标题
一个患有常染色体显性低钙化釉质生成不全的中国家族中的一种新的 FAM83H 突变
DOI：
10.1093/mutage/gey019
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发表时间：
2018-07-01
期刊：
影响因子：
2.7
通讯作者：
Zheng, Shuguo
中科院分区：
文献类型：
--
作者：
Yu, Shunlan;Quan, Junkang;Zheng, Shuguo
常染色体显性低钙化型釉质发育不全（ADHCAI）的特征是牙釉质质软，易崩解，暴露出深色的牙本质。ADHCAI是由一个名为序列相似性家族83成员H（FAM83H）的基因突变引起的。为了研究ADHCAI的分子遗传学，招募了一个三代人都患有ADHCAI的中国家庭。通过环境扫描电子显微镜（ESEM）对牙釉质超微结构进行分析，结果显示与健康对照组相比，ADHCAI患者的釉柱结构发生了改变。对FAM83H基因的突变分析在患病家庭成员中发现了一种新的无义突变（c.1222A>T），该突变在氨基酸第408位编码一个终止密码子，导致蛋白质过早截断（p.K408X）。体外绿色荧光蛋白（GFP）和FAM83H融合蛋白分析表明，在大鼠牙上皮SF2细胞和人胚肾293T细胞中，K408X突变阻止了FAM83H蛋白在细胞质中的正常积累。与野生型FAM83H蛋白在细胞质中的亚细胞定位相反，突变融合蛋白主要定位于细胞核。我们的研究结果提供了新的遗传学证据，表明FAM83H基因突变导致了ADHCAI。
Autosomal-dominant hypocalcification amelogenesis imperfecta (ADHCAI) is characterized by soft enamel that easily disintegrates and exposed dark dentin. ADHCAI is caused by mutations in a gene called family with sequence similarity 83 member H (FAM83H). To investigate the molecular genetics of ADHCAI, a Chinese family in which three generations exhibited ADHCAI was recruited. The enamel ultrastructure was analysed by environmental scanning electron microscopy (ESEM), which showed altered enamel rod (prism) structures in ADHCAI patients compared to the structures in healthy controls. Mutational analysis of the FAM83H gene identified a novel nonsense mutation (c.1222A>T) in the affected family members that encodes a stop codon at amino acid position 408, causing premature protein truncation (p. K408X). Green fluorescent protein (GFP) and FAM83H fusion protein analyses in vitro showed that normal cytoplasmic accumulation of the FAM83H protein was prevented by the K408X mutation in both rat dental epithelial SF2 cells and human embryonic kidney 293T cells. The mutant fusion protein localized primarily to the nucleus, in contrast to the cytoplasmic subcellular localization of the wild-type FAM83H protein. Our results provide new genetic evidence that mutations in FAM83H contribute to ADHCAI.