A Novel MBTPS2 Variant Associated With BRESHECK Syndrome Impairs Sterol-Regulated Transcription and the Endoplasmic Reticulum Stress Response

The study identified a novel Val256Leu variant in the MBTPS2 gene associated with BRESHECK syndrome, expanding the known genetic causes of this condition. This variant was found in a patient with additional symptoms such as bone marrow fibrosis, cytopenias, and chronic diarrhea, which were proposed as new manifestations of the syndrome. Functional assays demonstrated that this variant impaired sterol-regulated transcription and the endoplasmic reticulum stress response, similar to other known MBTPS2 variants. The findings suggested that Val256Leu represents a second causal allele for BRESHECK syndrome, highlighting the importance of MBTPS2 in the pathogenesis of this disorder and the need for further research to understand the mechanistic basis of these phenotypes.