Disruption of a DNA G-quadruplex causes a gain-of-function SCL45A1 variant relevant to developmental disorders  

作　　者：Yuxi Chen Jiang Long Sixian Wu Yazhen Wei Fei Yan Qing Li Jierui Yan Nannan Zhang Wenming Xu 

机构地区：[1]Joint Laboratory of Reproductive Medicine,Gynaecology and Paediatric Diseases and Birth Defects of Ministry of Education,West China Second University Hospital,Sichuan University,Chengdu 610041,China [2]The Mental Health Centre and the Psychiatric Laboratory,West China Hospital,Sichuan University,Chengdu 610041,China [3]National Centre for Birth Defect Monitoring,Key Laboratory of Birth Defects and Related Diseases of Women and Children,Ministry of Education,West China Second University Hospital,Sichuan University,Chengdu 610041,China [4]West China School of Pharmacy,Sichuan University,Chengdu 610041,China

出　　处：《Acta Biochimica et Biophysica Sinica》2024年第5期709-716,共8页生物化学与生物物理学报（英文版）

基　　金：supported by the grants from the Science and Technology Department of Sichuan Province(No.2021YJ0170);the Regional Innovation Cooperation Project of Sichuan Province(No.2022YFQ0100).

摘　　要：SLC45A1 encodes a glucose transporter protein highly expressed in the brain.Mutations in SLC45A1 may lead to neurological diseases and developmental disorders,but its exact role is poorly understood.DNA G-quadruplexes(DNA G4s)are stable structures formed by four guanine bases and play a role in gene regulation and genomic stability.Changes in DNA G4s may affect brain development and function.The mechanism linking alterations in DNA G-quadruplex structures to SLC45A1 pathogenicity remains unknown.In this study,we identify a functional DNA G-quadruplex and its key binding site on SLC45A1(NM_001080397.3:exon 2:c.449 G>A:p.R150K).This variant results in the upregulation of mRNA and protein expression,which may lead to intellectual developmental disorder with neuropsychiatric features.Mechanistically,the mutation is found to disrupt DNA G-quadruplex structures on SLC45A1,leading to transcriptional enhancement and a gain-of-function mutation,which further causes increased expression and function of the SLC45A1 protein.The identification of the functional DNA G-quadruplex and its effects on DNA G4s may provide new insights into the genetic basis of SLC45A1 pathogenicity and highlight the importance of DNA G4s of SLC45A1 in regulating gene expression and brain development.

关 键 词：SLC45A1 DNA G4 transcriptional enhancement gain of function 

分 类 号：R321[医药卫生—人体解剖和组织胚胎学]