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

encodes a glucose transporter protein highly expressed in the brain. Mutations in 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 pathogenicity remains unknown. In this study, we identify a functional DNA G-quadruplex and its key binding site on (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 , 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 pathogenicity and highlight the importance of DNA G4s of in regulating gene expression and brain development.