This blog sheds light on the significant role of signal peptides in protein synthesis and therapy development.
Signal peptides as key regulators of protein targeting and disease
Specific point mutations in signal peptides, short sequences guiding proteins to their correct cellular destinations, can be disease-causing. Recent studies have expanded our understanding of how these mutations can disrupt protein targeting, processing, and stability, leading to diverse pathologies.
Knowing how these mutations affect protein biogenesis can inform therapy development and signal peptide engineering, such as redirecting mislocalized therapeutic proteins and improving targeted delivery in gene therapy and vector design.
#1 Diabetes
Mutation in the preproinsulin signal peptide is associated with the onset of diabetes in newborns and children (1). These mutations are considered rare, accounting for <1% of patients classified as type 1 diabetic. Due to its clinical similarity to autoimmune type 1 diabetes, this form is often misdiagnosed, increasing the risk of unnecessary autoimmune interventions.
#2 Leydig cell hypoplasia
A variant in the signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis, associated with Leydig cell hypoplasia, a disorder that impairs male sexual development (2).
#3 Factor IX and Hemophilia B
Mutations in the signal peptide and propeptide of Factor IX (FIX) are associated with hemophilia B, a bleeding disorder. These mutations can impair FIX secretion and function (3).
#4 Isolated growth hormone deficiency
A mutation in the signal peptide of Growth Hormone Releasing Hormone Receptor (GHRHR) has been identified as a novel cause of isolated growth hormone deficiency, affecting growth and development. The identified mutation hinders the proper cleavage of the signal peptide, preventing GHRHR from translocating to the cell surface. The signal peptide is essential for the proper localization of nascent GHRHR to the endoplasmic reticulum (4).
#5 Prion disease
A point mutation in the GPI-attachment signal peptide of the prion protein (PrPC) has been found to accelerate the development of prion disease, a rare neurodegenerative condition that presents with imbalance, memory loss, and psychiatric symptoms (5). Once the symptoms appear, the disease progresses very quickly and is usually fatal within a few months of symptom onset.
Sources:
1. Bonfanti, et al. (2009). Insulin gene mutations as cause of diabetes in children negative for five type 1 diabetes autoantibodies. Diabetes Care 32, 123–125.
2. Vezzoli et al. (2015). A new variant in signal peptide of the human luteinizing hormone receptor (LHCGR) affects receptor biogenesis causing leydig cell hypoplasia. Hum. Mol. Genet. 24, 6003–6012.
3. Gao et al. (2020). Characterization of missensemutations in the signal peptide and propeptide of FIX in hemophilia B by acell-based assay. Blood Adv 2020; 4 (15).
4. Godi et al. (2009). A Recurrent Signal Peptide Mutation in the Growth Hormone Releasing Hormone Receptor with Defective Translocation to the Cell Surface and Isolated Growth Hormone Deficiency. JCEM,Vol 94, Issue 10.
5. Kobayashi et al. (2023). A point mutation in GPI-attachment signal peptide accelerates the development of prion disease. ActaN europathol. 145, 637–650
