Khan Sher Alam, Khan Saadullah, Muhammad Noor, Rehman Zia Ur, Khan Muhammad Adnan, Nasir Abdul, Kalsoom Umm-E-, Khan Anwar Kamal, Khan Hassan, Wasif Naveed
Department of Biotechnology and Genetic Engineering, Kohat University of Science and Technology (KUST), Kohat, Pakistan.
Dental Material, Institute of Basic Medical Sciences, Khyber Medical University Peshawar, Peshawar, Pakistan.
Front Genet. 2022 Jan 25;12:782653. doi: 10.3389/fgene.2021.782653. eCollection 2021.
The syndromic and non-syndromic congenital missing teeth phenotype is termed tooth agenesis. Since tooth agenesis is a heterogeneous disorder hence, the patients show diverse absent teeth phenotypes. Thus identifying novel genes involved in the morphogenesis of ectodermal appendages, including teeth, paves the way for establishing signaling pathways. We have recruited an autosomal recessive non-syndromic tooth agenesis family with two affected members. The exome sequencing technology identified a novel missense sequence variant c.1421T > C; p.(Ile474Thr) in a regulatory factor X (RFX) family member (RFX2, OMIM: 142,765). During the data analysis eight rare variants on various chromosomal locations were identified, but the co-segregation analysis using Sanger sequencing confirmed the segregation of only two variants : c.1421T > C; p.(Ile474Thr), : c.109C > G; p.(Pro37Ala) lying in a common 7.1 MB region of homozygosity on chromosome 19p13.3. Furthermore, the online protein prediction algorithms and protein modeling analysis verified the variant as a damaging genetic alteration and ACMG pathogenicity criteria classified it as likely pathogenic. On the other hand, the variant showed benign outcomes. regulates the Hedgehog and fibroblast growth factor signaling pathways, which are involved in the epithelial and mesenchymal interactions during tooth development. Prior animal model studies have confirmed the expression of at a developmental stage governing mouth formation. Moreover, its regulatory role and close association with ciliary and non-ciliary genes causing various dental malformations makes it a potential candidate gene for tooth agenesis phenotype. Further studies will contribute to exploring the direct role of in human tooth development.
综合征型和非综合征型先天性缺牙表型被称为牙齿发育不全。由于牙齿发育不全是一种异质性疾病，因此患者表现出多种缺牙表型。因此，鉴定参与包括牙齿在内的外胚层附属器形态发生的新基因，为建立信号通路铺平了道路。我们招募了一个常染色体隐性非综合征型牙齿发育不全家族，有两名受影响成员。外显子组测序技术在一个调节因子X（RFX）家族成员（RFX2，OMIM：142,765）中鉴定出一个新的错义序列变异c.1421T>C；p.(Ile474Thr)。在数据分析过程中，鉴定出了位于不同染色体位置的8个罕见变异，但使用桑格测序进行的共分离分析仅证实了两个变异的共分离：c.1421T>C；p.(Ile474Thr)，：c.109C>G；p.(Pro37Ala)，它们位于19号染色体p13.3上一个常见的7.1兆碱基纯合区域。此外，在线蛋白质预测算法和蛋白质建模分析证实该变异是一种有害的基因改变，美国医学遗传学与基因组学学会（ACMG）的致病性标准将其归类为可能致病。另一方面，该变异显示出良性结果。 调节刺猬信号通路和成纤维细胞生长因子信号通路，这两条信号通路在牙齿发育过程中参与上皮和间充质相互作用。先前的动物模型研究已证实在控制口腔形成的发育阶段有表达。此外，它的调节作用以及与导致各种牙齿畸形的纤毛和非纤毛基因的密切关联，使其成为牙齿发育不全表型的一个潜在候选基因。进一步的研究将有助于探索 在人类牙齿发育中的直接作用。
