Functional characterization of non-coding variants in disease-causing regions of benign choreoathetosis (CAHTP) and thyroid dysgenesis (CHTD)

良性舞蹈手足徐动症 (CAHTP) 和甲状腺发育不全 (CHTD) 致病区域非编码变异的功能特征

• 批准号: 426112492
• 负责人: Professor Dr. Heiko Krude
• 金额: --
• 依托单位: Institut für Experimentelle Pädiatrische Endokrinologie
• 依托单位国家: 德国
• 项目类别: Research Units
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/426112492?language=en
• 关键词: Functional; characterization; non; coding; variants

The transcription factor NKX2-1 is a master regulator not only of thyroid follicular cells, but also of specific neuronal cell types in the ventral telencephalon, the diencephalon, and of pulmonary alveolar epithelial cells. Mutations of the NKX2-1 gene cause benign choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction (CAHTP, OMIM #610978), an autosomal dominant disorder with variable penetrance and severity of thyroid and pulmonary phenotypes; as initially shown by our group already in 2002. During the first funding period we used WGS to identify non-coding variants in the NKX2-1 gene locus of a cohort of CAHTP patients with an intact NKX2-1 gene. By analyzing epigenomic signatures of the NKX2-1 gene locus, we assigned a putative 100 kb disease-associated region at 14q13 downstream of the NKX2-1 gene. In the first part of this project, we will target this region with different techniques to examine the cis-regulatory role of this genomic region and to analyze the impact of the non-coding variants detected by WGS in our cohort of 25 CAHTP index patients. To gain additional insights into the genetic mechanisms of thyroid dysgenesis (CHTD), we conducted a collaborative genome-wide association study (GWAS) with Satoshi Narumi from Keio University School of Medicine, Tokyo (Japan) and identified a first disease-associated region for CHTD in a non-coding genomic region at 2q33.3. The significant top genotyped SNP (rs9789446) was located in a 72 kb intronic region that contains cis-regulatory sequences for FZD5 and CCNYL1 expression in thyroid tissue as inferred from a combination of epigenome, transcriptome, and chromatin interaction data sets. To begin to formally demonstrate the disease relevance of this non-coding region for thyroid dysgenesis, we will characterize the activity of putative of cis-regulatory elements at 2q33.3 in the second funding period of this project.

转录因子NKX 2 -1不仅是甲状腺滤泡细胞的主调节因子，而且是腹侧端脑、间脑和肺泡上皮细胞中特定神经元细胞类型的主调节因子。NKX 2 -1基因突变可引起良性舞蹈徐动症和先天性甲状腺功能减退症，伴或不伴肺功能障碍（CAHTP，OMIM #610978），这是一种常染色体显性遗传疾病，甲状腺和肺表型的频率和严重程度可变;正如我们的研究小组在2002年首次显示的那样。在第一个资助期内，我们使用WGS来鉴定NKX 2 - 1基因完整的CAHTP患者队列的NKX 2 - 1基因位点的非编码变体。通过分析NKX 2 -1基因位点的表观基因组特征，我们在NKX 2 -1基因下游14 q13处分配了一个推定的100 kb疾病相关区域。在本项目的第一部分，我们将用不同的技术靶向该区域，以检查该基因组区域的顺式调节作用，并分析WGS检测到的非编码变体对我们的25例CAHTP指数患者队列的影响。为了获得对甲状腺发育不全（CRTD）遗传机制的更多见解，我们与日本东京庆应义塾大学医学院的Satoshi Narumi进行了一项全基因组关联研究（GWAS），并在2q33.3的非编码基因组区域中确定了CRTD的第一个疾病相关区域。显着的顶部基因型SNP（rs 9789446）位于一个72 kb的内含子区域，其中包含FZD 5和CCNYL 1在甲状腺组织中表达的顺式调控序列，从表观基因组，转录组和染色质相互作用数据集的组合推断。为了开始正式证明该非编码区与甲状腺发育不全的疾病相关性，我们将在本项目的第二个资助期内描述2q33.3处推定顺式调节元件的活性。