Deep Intronic Mutation in SERPING1 Caused Hereditary Angioedema Through Pseudoexon Activation.

Area of Science:

• Genetics
• Molecular Biology
• Immunology

Background:

• Hereditary angioedema (HAE) is a rare, life-threatening autosomal dominant disorder.
• It is linked to C1 inhibitor deficiency (Type I) or dysfunction (Type II), often due to SERPING1 mutations.
• Standard genetic analysis sometimes fails to identify the causal mutation.

Purpose of the Study:

• To identify the genetic cause of HAE in a family where conventional methods failed.
• To characterize a novel mutation and its mechanism in the SERPING1 gene.
• To investigate potential mutation hotspots within SERPING1 intron 6.

Main Methods:

• Advanced molecular genetic analysis.
• Deep intronic sequencing of the SERPING1 gene.
• Analysis of aberrant transcripts and splice site mutations.

Main Results:

• A novel deep intronic mutation, c.1029+384A>G, in SERPING1 intron 6 was identified as the cause of HAE type I.
• This mutation creates a new splice donor site, leading to pseudoexon inclusion—a novel mechanism in SERPING1.
• Intron 6 was found to contain other potential pseudoexon-activating sites and previously undescribed alternative exons.

Conclusions:

• Detecting low-abundant aberrant transcripts, often due to nonsense-mediated decay, requires specialized methods.
• SERPING1 intron 6 sequencing and tailored mRNA analysis are recommended for HAE diagnosis when coding sequences show no mutations.