SERPINA1 – Alpha-1 Antitrypsin Deficiency

SERPINA1 encodes alpha-1 antitrypsin (AAT), the primary serum protease inhibitor synthesized by hepatocytes. Deficiency of AAT (AATD) leads to unopposed neutrophil elastase activity in the lung, causing panacinar emphysema, and to hepatocellular accumulation of misfolded protein, resulting in chronic liver disease and cirrhosis. The association between SERPINA1 variants and AATD is well established and informs both respiratory and hepatic clinical management.

AATD is inherited in an autosomal co-dominant manner with both alleles contributing to circulating AAT levels. Over 400 unrelated probands, including 258 Pi*ZZ homozygotes, 74 Pi*SZ compound heterozygotes, and 86 individuals with rare deficiency alleles, have been described (PMID:25938293). Segregation of pathogenic alleles with disease phenotype has been documented in multiple multi-generation pedigrees involving at least 19 affected relatives (PMID:22078084).

The variant spectrum encompasses common missense alleles—Pi*Z (c.1096G>A (p.Glu366Lys)), Pi*S (c.863A>T (p.Glu288Val))—as well as null alleles (e.g., c.1158dup (p.Glu387ArgfsTer14)) and over 200 rare or population-specific mutations (PMID:38388492). Recurrent frameshift and splice-site variants have been reported across diverse ethnicities, and founder mutations such as Q0Ourém and Q0Milano underline the importance of comprehensive genetic testing. Population carrier frequency for Pi*Z reaches 2–5% in Europeans (PMID:18294358).

Functional studies demonstrate that the Z variant misfolds and polymerizes within the endoplasmic reticulum, triggering hepatocellular injury and reduced secretion (PMID:9070606). In PiZ transgenic mice, mutant Z accumulation correlates with caspase activation and hepatocyte apoptosis (PMID:17886264), while rapamycin-induced autophagy reduces intrahepatic Z polymers and liver fibrosis (PMID:20511674). In vitro analyses confirm that null variants lead to complete loss of inhibitory activity, and missense alleles alter protein stability and elastase association kinetics.

Some M-like variants, such as PLowell (c.230C>T (p.Ser77Phe)), exhibit near-normal serum levels but reduced elastase inhibition, illustrating qualitative dysfunction and diagnostic pitfalls of phenotype-only assays (PMID:8770333). These findings underscore the necessity of integrating genotyping with biochemical and clinical assessment.

Collectively, the genetic and experimental evidence fulfills ClinGen criteria for a Definitive gene–disease relationship. SERPINA1 variant analysis is essential for confirming AATD, guiding augmentation therapy, and assessing family risk. Key take-home: SERPINA1 genetic testing provides definitive diagnosis of AATD, enabling timely intervention to mitigate pulmonary and hepatic complications.

References

• American Journal of Medical Genetics • 2001 • Molecular analysis of the Pi*Z allele in patients with liver disease. PMID:11754061
• Australian and New Zealand Journal of Medicine • 1995 • Alpha-1-antitrypsin PLowell: a normally functioning variant present in low concentration. PMID:8770333
• Hepatology • 2007 • Alpha-1-antitrypsin mutant Z protein content in individual hepatocytes correlates with cell death in a mouse model. PMID:17886264
• Experimental Biology and Medicine • 2010 • Rapamycin reduces intrahepatic alpha-1-antitrypsin mutant Z protein polymers and liver injury in a mouse model. PMID:20511674
• COPD • 2015 • Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation. PMID:25938293
• American Journal of Respiratory Cell and Molecular Biology • 1997 • alpha1-antitrypsin gene mutation hot spot associated with the formation of a retained and degraded null variant. PMID:9070606
• Orphanet Journal of Rare Diseases • 2024 • Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review. PMID:38388492

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