Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.
Department of Dentistry, School of Dentistry, National Taiwan University, Jhongjheng District, Taipei City, Taiwan.
J Dent Res. 2021 Mar;100(3):293-301. doi: 10.1177/0022034520962731. Epub 2020 Oct 9.
Autosomal dominant hypocalcified amelogenesis imperfecta (ADHCAI; OMIM #130900) is a genetic disorder exhibiting severe hardness defects and reduced fracture toughness of dental enamel. While the condition is nonsyndromic, it can be associated with other craniofacial anomalies, such as malocclusions and delayed or failed tooth eruption. Truncation mutations in (OMIM 611927) are hitherto the sole cause of ADHCAI. With human genetic studies, knockout and mutation-knock-in mouse models indicated that FAM83H does not serve a critical physiologic function during enamel formation and suggested a neomorphic mutation mechanism causing ADHCAI. The function of FAM83H remains obscure. FAM83H has been shown to interact with various isoforms of casein kinase 1 (CK1) and keratins and to mediate organization of keratin cytoskeletons and desmosomes. By considering FAM83H a scaffold protein to anchor CK1s, further molecular characterization of the protein could gain insight into its functions. In this study, we characterized 9 kindreds with ADHCAI and identified 3 novel truncation mutations: p.His437, p.Gln459*, and p.Glu610*. Some affected individuals exhibited hypoplastic phenotypes, in addition to the characteristic hypocalcification enamel defects, which have never been well documented. Failed eruption of canines or second molars in affected persons was observed in 4 of the families. The p.Glu610* mutation was located in a gap area (amino acids 470 to 625) within the zone of previously reported pathogenic variants (amino acids 287 to 694). In vitro pull-down studies with overexpressed FAM83H proteins in HEK293 cells demonstrated an interaction between FAM83H and SEC16A, a protein component of the COP II complex at endoplasmic reticulum exit sites. The interaction was mediated by the middle part (amino acids 287 to 657) of mouse FAM83H protein. Results of this study significantly extended the phenotypic and genotypic spectrums of -associated ADHCAI and suggested a role for FAM83H in endoplasmic reticulum-to-Golgi vesicle trafficking and protein secretion (dbGaP phs001491.v1.p1).
常染色体显性低钙性牙釉质不全症（ADHCAI；OMIM#130900）是一种遗传疾病，表现为严重的硬度缺陷和牙釉质断裂韧性降低。虽然这种情况是非综合征性的，但它可能与其他颅面异常有关，如错颌畸形和牙齿延迟或失败萌出。到目前为止，（OMIM611927）截断突变是 ADHCAI 的唯一原因。通过人类遗传研究，FAM83H 基因敲除和突变敲入小鼠模型表明，FAM83H 在釉质形成过程中不发挥关键的生理功能，并提示一种新的突变机制导致 ADHCAI。FAM83H 的功能仍然不清楚。已经表明 FAM83H 与各种酪蛋白激酶 1（CK1）和角蛋白的同工型相互作用，并介导角蛋白细胞骨架和桥粒的组织。通过将 FAM83H 视为锚定 CK1s 的支架蛋白，可以进一步对该蛋白进行分子特征分析，从而深入了解其功能。在这项研究中，我们对 9 个 ADHCAI 家系进行了特征描述，并鉴定出 3 种新的截断突变：p.His437、p.Gln459和 p.Glu610。一些受影响的个体除了具有特征性的低钙牙釉质缺陷外，还表现出发育不良的表型，这从未得到很好的记录。在 4 个家系中观察到尖牙或第二磨牙萌出失败。p.Glu610*突变位于先前报道的致病性变异（氨基酸 287 至 694）区的间隙区（氨基酸 470 至 625）内。用 HEK293 细胞中转染的过表达 FAM83H 蛋白进行体外下拉研究表明，FAM83H 与 SEC16A 之间存在相互作用，SEC16A 是内质网出口位点 COP II 复合物的蛋白成分。这种相互作用是由小鼠 FAM83H 蛋白的中间部分（氨基酸 287 至 657）介导的。这项研究的结果显著扩展了与 FAM83H 相关的 ADHCAI 的表型和基因型谱，并表明 FAM83H 在内质网到高尔基体囊泡运输和蛋白质分泌中起作用（dbGaP phs001491.v1.p1）。
