MBTPS2-related diseases are caused by hemizygous or rarely heterozygous (females) pathogenic variants in MBTPS2. Most causal variants are missense, but there are reports of splice and frameshift variants. MBTPS2 (membrane-bound transcription factor protease, site 2) encodes the protein S2P (site 2 protease), a zinc finger protease with a critical role in the Endoplasmic reticulum (ER) stress/unfolded protein response and activation of de novo cholesterol biosynthesis in response to cholesterol paucity. It is unknown whether the clinical phenotypes of MBTPS2-related diseases are driven by impaired ER stress response and/or cholesterol biosynthesis defects. Diagnosis is typically made by gene panel (intellectual disability panel, bone fragility/osteogenesis imperfecta panel, ectodermal dysplasia/ichthyosis gene panel) or exome sequencing.
MBTPS2