MBTPS2-related diseases are rare, X-linked recessive genetic disorders with some manifesting females that fall into 4 phenotypically-overlapping categories: (1) ichthyosis follicularis, atrichia, and photophobia (IFAP) syndrome with and without BRESHECK syndrome, characterized by congenital ichthyosis follicularis, alopecia, and photophobia with or without structural brain differences, intellectual disability, genitourinary malformations, structural heart disease, orofacial clefting, growth failure, skeletal abnormalities, and Hirschsprung disease, (2) keratosis follicularis spinulosa decalvans (KFSD) characterized by hyperkeratosis of the palms and soles, sparse hair, and photophobia, (3) Olmstead syndrome characterized by alopecia and mutilating plantopalmar keratoderma, (4), and Osteogenesis imperfecta characterized by recurrent fractures and brittle bones. Causal variants are dispersed throughout the gene/protein without a clear genotype-phenotype correlation, but there is some suggestion that variants within or near transmembrane domains 5 and 8 cause more severe disease.
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.
MBTPS2