Graduate Institute of Clinical Dentistry, National Taiwan University School of Dentistry, Taipei City, Taiwan.
Department of Dentistry, National Taiwan University Hospital, Taipei City, Taiwan.
J Dent Res. 2021 Jul;100(8):868-874. doi: 10.1177/0022034521996620. Epub 2021 Mar 14.
Hereditary gingival fibromatosis (HGF) is a rare genetic disorder featured by nonsyndromic pathological overgrowth of gingiva. The excessive gingival tissues can cause dental, masticatory, and phonetic problems, which impose severe functional and esthetic burdens on affected individuals. Due to its high recurrent rate, patients with HGF have to undergo repeated surgical procedures of gingival resection, from childhood to adulthood, which significantly compromises their quality of life. Unraveling the genetic etiology and molecular pathogenesis of HGF not only gains insight into gingival physiology and homeostasis but also opens avenues for developing potential therapeutic strategies for this disorder. Recently, mutations in (OMIM 600571), encoding a transcription repressor, were reported to cause HGF (GINGF5; OMIM #617626) in 3 Turkish families. However, the functions of REST in gingival homeostasis and pathogenesis of -associated HGF remain largely unknown. In this study, we characterized 2 HGF families and identified 2 novel mutations, c.2449C>T (p.Arg817) and c.2771_2793dup (p.Glu932Lysfs*3). All 5 mutations reported to date are nonsenses or frameshifts in the last exon of and would presumably truncate the protein. In vitro reporter gene assays demonstrated a partial or complete loss of repressor activity for these truncated RESTs. When coexpressed with the full-length protein, the truncated RESTs impaired the repressive ability of wild-type REST, suggesting a dominant negative effect. Immunofluorescent studies showed nuclear localization of overexpressed wild-type and truncated RESTs in vitro, indicating preservation of the nuclear localization signal in shortened proteins. Immunohistochemistry demonstrated a comparable pattern of ubiquitous REST expression in both epithelium and lamina propria of normal and HGF gingival tissues despite a reduced reactivity in HGF gingiva. Results of this study confirm the pathogenicity of truncation mutations occurring in the last exon causing HGF and suggest the pathosis is caused by an antimorphic (dominant negative) disease mechanism.
遗传性牙龈纤维瘤病（Hereditary gingival fibromatosis，HGF）是一种罕见的遗传性疾病，其特征为牙龈的非综合征性病理性过度生长。过多的牙龈组织会导致牙齿、咀嚼和发音问题，给患者带来严重的功能和美观负担。由于 HGF 的复发率很高，患者从儿童期到成年期都需要进行多次牙龈切除术，这极大地影响了他们的生活质量。阐明 HGF 的遗传病因和分子发病机制不仅有助于深入了解牙龈的生理和稳态，还为开发这种疾病的潜在治疗策略提供了途径。最近，在 3 个土耳其家庭中，报道了编码转录抑制因子的基因突变导致 HGF（GINGF5；OMIM #617626）。然而，REST 在牙龈稳态和 - 相关 HGF 发病机制中的功能仍知之甚少。在这项研究中，我们对 2 个 HGF 家系进行了特征描述，并鉴定出 2 个新的 突变，c.2449C>T（p.Arg817*）和 c.2771_2793dup（p.Glu932Lysfs*3）。迄今为止报道的所有 5 个突变均位于 的最后一个外显子中，且为无义或移码突变，推测会导致蛋白截短。体外报告基因检测表明，这些截短的 REST 丧失了部分或完全的抑制活性。当与全长蛋白共表达时，截短的 REST 会损害野生型 REST 的抑制能力，提示存在显性负效应。免疫荧光研究表明，体外过表达的野生型和截短型 REST 均定位于细胞核，表明缩短的蛋白保留了核定位信号。免疫组织化学显示，正常和 HGF 牙龈组织的上皮和固有层中均存在普遍表达的 REST，尽管 HGF 牙龈组织中的反应性降低，但表达模式相似。本研究结果证实了发生在最后一个外显子中的 截断突变导致 HGF 的致病性，并提示该疾病是由一种抗形（显性负）疾病机制引起的。
