Department of General Dentistry, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
College of Stomatology, Shanghai Jiao Tong University, Shanghai, China.
Clin Oral Investig. 2024 Apr 30;28(5):287. doi: 10.1007/s00784-024-05659-6.
Coffin-Siris Syndrome (CSS) is a congenital disorder characterized by delayed growth, dysmorphic facial features, hypoplastic nails and phalanges of the fifth digit, and dental abnormalities. Tooth agenesis has been reported in CSS patients, but the mechanisms regulating this syndromic tooth agenesis remain largely unknown. This study aims to identify the pathogenic mutation of CSS presenting tooth genesis and explore potential regulatory mechanisms.
We utilized whole-exome sequencing to identify variants in a CSS patient, followed by Sanger validation. In silico analysis including conservation analysis, pathogenicity predictions, and 3D structural assessments were carried out. Additionally, single-cell RNA sequencing and fluorescence in situ hybridization (FISH) were applied to explore the spatio-temporal expression of Sox4 expression during murine tooth development. Weighted Gene Co-expression Network Analysis (WGCNA) was employed to examine the functional role of SOX4.
A novel de novo SOX4 missense mutation (c.1255C > G, p.Leu419Val) was identified in a Chinese CSS patient exhibiting tooth agenesis. Single-cell RNA sequencing and FISH further verified high expression of Sox4 during murine tooth development, and WGCNA confirmed its central role in tooth development pathways. Enriched functions included cell-substrate junctions, focal adhesion, and RNA splicing.
Our findings link a novel SOX4 mutation to syndromic tooth agenesis in CSS. This is the first report of SOX4 missense mutation causing syndromic tooth agenesis.
This study not only enhances our understanding of the pathogenic mutation for syndromic tooth agenesis but also provides genetic diagnosis and potential therapeutic insights for syndromic tooth agenesis.
颅骨锁骨发育不全综合征（CSS）是一种先天性疾病，其特征为生长迟缓、颜面畸形、第五指指甲和指骨发育不全以及牙齿异常。CSS 患者存在牙齿缺失，但调控这种综合征性牙齿缺失的机制仍知之甚少。本研究旨在鉴定发生牙齿缺失的 CSS 的致病突变，并探索潜在的调控机制。
我们采用全外显子组测序鉴定了一名 CSS 患者的变异，随后进行 Sanger 验证。采用保守性分析、致病性预测和三维结构评估等方法进行了体外分析。此外，还应用单细胞 RNA 测序和荧光原位杂交（FISH）技术，探索 Sox4 在小鼠牙齿发育过程中的时空表达。采用加权基因共表达网络分析（WGCNA），检测 SOX4 的功能作用。
在一名患有牙齿缺失的中国 CSS 患者中发现了一个新的 SOX4 错义突变（c.1255C>G，p.Leu419Val）。单细胞 RNA 测序和 FISH 进一步验证了 Sox4 在小鼠牙齿发育过程中的高表达，WGCNA 则证实了其在牙齿发育途径中的核心作用。富集的功能包括细胞-基底连接、焦点黏附以及 RNA 剪接。
本研究将一个新的 SOX4 突变与 CSS 的综合征性牙齿缺失联系起来。这是首例报道的 SOX4 错义突变导致综合征性牙齿缺失。
本研究不仅增进了我们对综合征性牙齿缺失致病突变的认识，还为综合征性牙齿缺失提供了遗传诊断和潜在的治疗思路。
