# Functional characterization of pathogenic SATB2 missense variants identifies distinct effects on chromatin binding and transcriptional activity

## TL;DR

This study explores how specific SATB2 gene mutations affect chromatin binding and gene activity, revealing diverse effects that go beyond simple loss of function.

## Contribution

The study functionally characterizes SATB2 missense variants, identifying distinct effects on chromatin binding and transcriptional activity.

## Key findings

- Most SATB2 missense variants show partial loss-of-function effects.
- Eight variants exhibit increased SATB2 function with stronger DNA co-localization and transcriptional activity.
- Results suggest molecular heterogeneity in SATB2-associated syndrome beyond haploinsufficiency.

## Abstract

SATB2-associated syndrome is an autosomal dominant neurodevelopmental syndrome caused by genetic alterations in the transcription factor SATB2. The associated phenotype is variable, and genotype-phenotype correlation studies have not yet been able to explain differences in severity and symptoms across affected individuals. While haploinsufficiency is the most often described disease mechanism, with the majority of variants consisting of whole- or partial-gene deletions and protein truncating variants with predicted loss of function, approximately one-third of affected individuals carry a SATB2 missense variant with an unknown effect. In this study, we sought to functionally characterize these missense variants to uncover associated pathogenic mechanisms. We combined a set of human cell-based experiments to screen 31 etiological SATB2 missense variants for effects on nuclear localization, global chromatin binding, and transcriptional activity. Our data indicate partial loss-of-function effects for most of the studied missense variants but identify at least eight variants with increased SATB2 function showing a combination (or subset) of features that include stronger co-localization with DNA, decreased nuclear protein mobility suggesting increased overall chromatin binding, and maintained or increased transcriptional activity. These results demonstrate that phenotypes associated with variants in SATB2 may have distinct underlying disease mechanisms, and the data could provide a resource for future studies investigating disease variability and potential therapies for this condition.

Systematic analysis of etiological SATB2 missense variants associated with SATB2-associated syndrome reveals distinct effects on chromatin binding and transcriptional activity. These findings highlight molecular heterogeneity and suggest functional consequences beyond haploinsufficiency. The results provide a resource for future studies into SATB2 variant interpretation and potential contributions to disease variability.