REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis
REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis
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DOI：
10.1016/j.ajhg.2017.06.006
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发表时间：
2017-07-06
影响因子：
9.8
通讯作者：
Lupski, James R.
中科院分区：
文献类型：
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作者：
Bayram, Yavuz;White, Janson J.;Lupski, James R.
遗传性牙龈纤维瘤病(HGF)是牙龈纤维瘤病最常见的遗传形式，它发展为一种缓慢进展的、良性的、局限性的或全面性的角化性牙龈增大。HGF是一种遗传异质性疾病，既可以常染色体显性遗传，也可以常染色体隐性遗传，也可以零星出现。到目前为止，已有4个基因座(2p22.1、2p23.3-p22.3、5q13-q22和11p15)被定位到常染色体上，其中一个基因(SOS1)与肝细胞生长因子以显性遗传方式分离。在这里，我们报告了来自三个无关家庭的11名HGF患者。全外显子组测序(WES)在所有家系的先证者中发现了三种不同的截断突变，包括两个移码和一个RE1沉默转录因子(REST)无义变异，进一步的遗传和基因组分析证实了WES的发现。REST是一种转录抑制因子，在全身表达；它在不同的细胞环境中扮演不同的角色，如致癌和肿瘤抑制功能，以及造血和心脏分化。在这里，我们展示了在REST中的生殖系最终剔除突变对生物体发育的影响以及与HGF表型的关联。
Hereditary gingival fibromatosis (HGF) is the most common genetic form of gingival fibromatosis that develops as a slowly progressive, benign, localized or generalized enlargement of keratinized gingiva. HGF is a genetically heterogeneous disorder and can be transmitted either as an autosomal-dominant or autosomal-recessive trait or appear sporadically. To date, four loci (2p22.1, 2p23.3-p22.3, 5q13-q22, and 11p15) have been mapped to autosomes and one gene (SOS1) has been associated with the HGF trait observed to segregate in a dominant inheritance pattern. Here we report 11 individuals with HGF from three unrelated families. Whole-exome sequencing (WES) revealed three different truncating mutations including two frameshifts and one nonsense variant in RE1-silencing transcription factor (REST) in the probands from all families and further genetic and genomic analyses confirmed the WES-identified findings. REST is a transcriptional repressor that is expressed throughout the body; it has different roles in different cellular contexts, such as oncogenic and tumor-suppressor functions and hematopoietic and cardiac differentiation. Here we show the consequences of germline final-exontruncating mutations in REST for organismal development and the association with the HGF phenotype.