Site-1 Protease Deficiency Causes Human Skeletal Dysplasia

Abstract

Mannose-6-phosphate (M6P) is a posttranslational modification on N-linked glycans on lysosomal hydrolases in the Golgi apparatus, which is required for selective transport of lysosomal hydrolases from the Golgi apparatus to lysosomes via M6P receptors. Defects in M6P modification by genetic manipulations or in hereditary genetic disorders result in abnormal extracellular secretion of lysosomal hydrolases and are thus the basis of the pathogenesis of lysosome storage diseases. N-acetylglucosamine (GlcNAc)-1-phosphotransferase, an enzyme catalyzing M6P modification, is synthesized as an inert form that requires proteolytic activation by the Golgi-localized protease, site-1 protease (S1P). S1P, encoded by membrane-bound transcription factor peptidase, site 1 (MBTPS1), is ubiquitously expressed and functions sequentially with the site-2 protease to proteolytically activate unique membrane-bound latent transcription factors in the Golgi apparatus. These transcription factors include sterol regulatory element-binding protein required for inducing lipogenesis, and activating transcription factor 6 required for inducing endoplasmic reticulum stress-related unfolded protein response. Since we reported the first patient with MBTPS1 pathogenic variants who has congenital skeletal dysplasia due to compound endoplasmic reticulum and lysosomal dysfunctions, there have been a few reports regarding novel MBTPS1 variants worldwide. Here we overview genotype-phenotype relationships in so far reported patients with MBTPS1 variants.