Disorders with similar clinical phenotypes reveal underlying genetic interaction: SATB2 acts as an activator of the UPF3B gene

Abstract

Two syndromic cognitive impairment disorders have very similar craniofacial dysmorphisms. One is caused by mutations of SATB2, a transcription regulator, and the other by heterozygous mutations leading to premature stop codons in UPF3B, encoding a member of the nonsense-mediated mRNA decay complex. Here we demonstrate that the products of these two causative genes function in the same pathway. We show that the SATB2 nonsense mutation in our patient leads to a truncated protein that localizes to the nucleus, forms a dimer with wild-type SATB2 and interferes with its normal activity. This suggests that the SATB2 nonsense mutation has a dominant negative effect. The patient’s leukocytes had significantly decreased UPF3B mRNA compared to controls. This effect was replicated both in vitro, where siRNA knockdown of SATB2 in HEK293 cells resulted in decreased UPF3B expression, and in vivo, where embryonic tissue of Satb2 knock-out mice showed significantly decreased Upf3b expression. Furthermore, chromatin immunoprecipitation demonstrates that SATB2 binds to the UPF3B promoter, and a luciferase reporter assay confirmed that SATB2 expression significantly activates gene transcription using the UPF3B promoter. These findings indicate that SATB2 acts as an activator UPF3B expression through binding to its promoter. This study emphasizes the value of recognizing disorders with similar clinical phenotypes to explore underlying mechanisms of genetic interaction.

Further delineation of the SATB2 phenotype

“…A very recently published follow-up study of Leoyklang et al 27 including immunoblot analyses further supports Figure 1 for the extents of the deletions. All of these patients that clearly show the SATB2-associated phenotype have severe ID including delayed to non-existent speech development, cleft palate or *assumably high-arched palate (unfortunately, not reported sufficiently), micrognathia and tooth abnormalities.…”

Genotype and phenotype in 12 additional individuals with SATB2‐associated syndrome

“…Alterations in the SATB2 gene can result from a variety of different mechanisms that include contiguous deletions, intragenic deletions and duplications, translocations with secondary gene disruption, and point pathogenic variants . We and others, have reported a total of 11 different SATB2 point pathogenic variants in 12 individuals with SAS . Here, we report on our joint experience with a series of 12 previously unpublished individuals and their genotypes, which include 10 novel pathogenic variants.…”

“…1 We and others, have reported a total of 11 different SATB2 point pathogenic variants in 12 individuals with SAS. [2][3][4][5][6][7][8] Here, we report on our joint experience with a series of 12 previously unpublished individuals and their genotypes, which include 10 novel pathogenic variants.…”

Genetics and genomics in Thailand: challenges and opportunities

“…), and SATB2 which causes a unique dysmorphic syndrome with intellectual deficit, SATB2 ‐associated syndrome (SAS) (Leoyklang et al. , ).…”