Functional Analyses of SATB2 Variants Reveal Pathogenicity Mechanisms Linked With SATB2-Associated Syndrome

SATB2-associated syndrome (SAS) is characterized by intellectual disability, neurodevelopmental disorders, cleft palate, and dental abnormalities. SAS is caused by variants in the special AT-rich sequence-binding protein 2 (SATB2), which encodes a transcription factor containing two CUT domains and a homeobox (HOX) domain. Here, we report the case of a 16-year-old male diagnosed with SAS using exome sequencing and investigate the functional consequences of previously reported SATB2 variants, including those in this case. The patient carried a heterozygous missense variant (c.1147G>C, p.A383P) in SATB2, which was predicted to be pathogenic in silico but was absent from public databases. Immunofluorescence assays demonstrated that SATB2 proteins with variants in the CUT2 domain predominantly localized to the cytoplasm. Functional analysis further revealed that wild-type SATB2 increased the activity of the Msx1 promoter, which is involved in palatogenesis and tooth development, whereas variants in the CUT1 domain disrupted this transcriptional activation. These findings suggest that the nuclear localization signal of SATB2 resides in the CUT2 domain and that Msx1 promoter impairment owing to SATB2 variants may contribute to the pathogenesis of cleft palate and tooth agenesis in SAS. This research highlights a novel pathogenic variant and the functional implications for understanding SAS.