Pathogenic signal peptide variants in the human genome

Area of Science:

• Genomics
• Molecular Biology
• Biochemistry

Background:

• Secreted and membrane proteins, crucial for cellular functions, rely on N-terminal signal peptides for targeting to the endoplasmic reticulum (ER).
• Mutations within signal peptides can impair protein targeting, translocation, processing, and stability, leading to various human diseases.
• Despite their importance, pathogenic signal peptide variants remain largely uncharacterized.

Purpose of the Study:

• To identify pathogenic signal peptide variants across the human genome using bioinformatic analyses.
• To predict the molecular mechanisms underlying the pathology caused by these variants.
• To establish a framework for connecting genomic mutations to human diseases.

Main Methods:

• Bioinformatic analysis of genomic data to identify signal peptide mutations.
• Classification of mutations based on predicted pathogenicity.
• In silico prediction of molecular mechanisms for pathogenic variants.

Main Results:

• Identification of over 65,000 signal peptide mutations, with over 11,000 classified as pathogenic.
• Pathogenic mutations identified in over 3,300 genes encoding secreted and membrane proteins.
• Most pathogenic mutations affect the hydrophobic core of the signal peptide, potentially triggering quality control mechanisms like Regulation of Aberrant Protein Production (RAPP) and mRNA degradation.
• Approximately 25% of pathogenic variants impact the N-terminal region or signal peptidase cleavage site, causing translocation defects or inhibiting protein processing.

Conclusions:

• A significant number of pathogenic signal peptide mutations have been identified and characterized.
• These mutations can disrupt critical protein processing steps, leading to disease.
• The study provides a framework for understanding the link between genomic mutations in signal peptides and human diseases.