A mutation in Site‐1 Protease is associated with a complex phenotype that includes episodic hyperCKemia and focal myoedema

Abstract

Background Site‐1 Protease (S1P) is a Golgi‐resident protein required for the activation of regulatory proteins that drive key cellular functions, including, the unfolded protein response (UPR) and lipid and cholesterol biosynthesis. While disruptions in S1P function have been widely characterized in animal models, to date, the implications of disrupted S1P function in human disease states are not completely known. Methods The patient and both parents underwent whole exome and mitochondrial DNA sequencing, and Sanger sequencing was used to confirm the mutation. Western blotting and immunofluorescence studies were performed on either proband‐derived fibroblasts or on an established cell line to assess protein expression and cellular localization of the mutated S1P protein. Quantitative real‐time PCR and luciferase reporter assays were used to examine activation of S1P target pathways in the context of the S1P mutation. Results We describe a female patient with a de novo heterozygous missense mutation in the transmembrane domain of S1P (p. Pro1003Ser). The patient presented to our neuromuscular clinic with episodic, activity‐induced, focal myoedema and myalgias with hyperCKemia. Her clinical phenotype was complex and included gastrointestinal hypomotility, ocular migraines, and polycystic ovary syndrome. Molecular analysis using proband‐derived fibroblasts and cell lines harboring the Pro1003Ser mutation demonstrated increased activation of UPR and lipid and cholesterol regulatory pathways and localization of S1P Pro1003Ser in the Golgi. Conclusion These findings suggest a critical function for S1P in several human organ systems and implicate an important role for S1P in various human disease states.

Spondyloepimetaphyseal dysplasia with elevated plasma lysosomal enzymes caused by homozygous variant in MBTPS1

“…There are few reports of phenotypes related to MBTPS1 . One study described heterozygous missense variant (de novo) in the transmembrane domain of S1P (p.Pro1003Ser) in an adult proband with episodic hyperCKemia and focal myoedema (Schweitzer et al, 2019), a phenotype markedly different from our proband. The different phenotype could be due to a gain‐of‐function caused by the MBTPS1 ‐p.Pro1003Ser variant instead of a LoF like in our proband.…”

The Differential Expression of Long Noncoding RNAs in Type 2 Diabetes Mellitus and Latent Autoimmune Diabetes in Adults

“…e gene encoding the proprotein-transferase family of subtilisin, which is localized to the cis/medial Golgi apparatus, regulates the homeostasis of cholesterol or lipid at alkaline residues via substrate lysing and plays an important role in regulating the formation of somatic cell division [21]. Following a review of the literature, the gene encoding S1P was speculated to affect the function of lysosomes and result in the development of DM.…”

Site-1 Protease inhibits mitochondrial metabolism by controlling the TGF-β target gene MSS51

“…function (21). To examine whether skeletal muscle-specific loss of S1P impacts mitochondrial function, we measured pyruvate-mediated mitochondrial respiration in the gastrocnemius of S1P smKO and WT mice.…”

“…Through RIP, S1P coordinates several important signaling pathways associated with human disease and organismal development (e.g., lipid/sterol biosynthesis, lysosomal biogenesis, and the unfolded protein response) (11)(12)(13)(14)(15)(16)(17)(18)(19)(20). We previously described a patient with a de novo, gain-of-function mutation in S1P who exhibited altered skeletal muscle mitochondrial morphology and myoedema (21). These findings suggested a (which was not certified by peer review) is the author/funder.…”