A novel SERPINA1 mutation causing serum alpha(1)-antitrypsin deficiency

Area of Science:

• Genetics
• Molecular Biology
• Biochemistry

Background:

• Alpha-1 Antitrypsin (α(1)AT) deficiency, caused by SERPINA1 gene mutations, is linked to pulmonary emphysema and liver disease.
• Prevalence in European ancestry is 1 in 2500 in the USA.
• α(1)AT deficiency is a significant health concern.

Purpose of the Study:

• To discover and characterize a novel SERPINA1 mutation.
• To investigate the functional consequences of this new mutation.
• To understand the molecular basis of α(1)AT deficiency in an underrepresented population.

Main Methods:

• Genetic sequencing to identify SERPINA1 mutations.
• Functional assays to assess protein secretion and aggregation.
• Analysis of protein structure and stability.

Main Results:

• Discovery of a novel 49 base pair deletion mutation (T379Δ) in the SERPINA1 gene.
• The T379Δ mutation causes a frameshift, altering the C-terminus of the α(1)AT protein.
• Functional studies revealed the mutant protein is retained intracellularly and aggregates.

Conclusions:

• The T379Δ mutation results in a non-secreted, aggregation-prone α(1)AT protein.
• This finding expands the known spectrum of SERPINA1 mutations and their associated deficiencies.
• Highlights the importance of genetic screening for α(1)AT deficiency in diverse populations.