Molecular basis of cblX syndrome

cblX 综合征的分子基础

• 批准号: 10692199
• 负责人: THOMAS M KRISTIE
• 金额: $ 39.93万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10692199
• 关键词: Biochemical; Cells; Cobalamin; Data Set; Development; Disease; Enzymes; Epigenetic Process; Epilepsy; Fibroblasts; Genes; Genetic Transcription; Genome; Homocystinuria; Intellectual functioning disability; Link; Metabolism; Molecular; Mutation; Neurologic; Pathway interactions; Patients; Phenotype; Proteins; Syndrome; Tissues; Transcription Coactivator; Vitamin B 12; clinical phenotype; host cell factor C1; methylmalonic aciduria; mouse model; promoter; recruit

Mutations in enzymes of the Vitamin B12/cobalamin metabolism or transport pathways can result in clinical phenotypes that include biochemical (methylmalonic aciduria, homocystinuria) and neurological presentations. A related syndrome, cblX, is characterized by a reduction of expression of a critical enzyme (MMACHC) in the cobalamin pathway and has been linked to mutations in the cellular transcriptional coactivator HCF-1. Similar to other cobalamin metabolism syndromes, CblX patients have a combination of severe developmental, biochemical, and neurological phenotypes (intellectual disability, epilepsy). However the full impacts of mutations in this coactivator and the molecular basis of cblX syndrome have not been investigated. In fiscal year 2022, data sets including global cellular transcription, HCF-1 occupancy of cellular gene promoters, and the epigenetic state of the genome were assessed and integrated from studies investigating the impacts of two distinct HCF-1 cblX mutations in mouse models of cblX syndrome. These analyses demonstrated that HCF-1 cblX mutations result in multiple biochemical disorders as well as misregulation of specific pathways that could contribute to cblX syndrome.

维生素B12/钴胺素代谢或转运途径的酶突变会导致临床表型，包括生化（甲基甲硅酸酸性尿液，同胞性肝炎）和神经系统表现。 相关综合征CBLX的特征是降低了钴胺素途径中临界酶（MMACHC）的表达，并且与细胞转录共激活器HCF-1中的突变有关。 与其他钴胺素代谢综合征类似，CBLX患者具有严重发育，生化和神经系统型（智力障碍，癫痫）的结合。 但是，尚未研究突变在该共激活因子和CBLX综合征的分子基础上的全部影响。 在2022财政年度，通过研究和整合了研究CBLX综合征小鼠模型小鼠模型中的两个不同的HCF-1 CBLX突变的影响，对研究和整合了包括全球细胞转录，细胞基因启动子的HCF-1占用率和基因组的表观遗传状态的数据集。 这些分析表明，HCF-1 CBLX突变会导致多种生化疾病以及可能导致CBLX综合征的特定途径的不正调。