Alpha-1 antitrypsin deficiency: Rare mutations

Dipl.-Biologist Martina Veith, PD Dr. med. Timm Greulich

The cause of alpha-1 antitrypsin deficiency (AAT deficiency) is mutations (alterations) in the SERPINA1 gene (serine protease inhibitor A1 gene), which is located on chromosome 14. The AAT gene exhibits considerable genetic variability. Currently, over 100 different mutations of the SERPINA1 gene are known, including many rare mutations that can lead to structural changes in AAT and thus to clinical presentations of varying severity. Mutations in this gene can, but do not necessarily, lead to AAT deficiency. Depending on the type and location of the mutation on the SERPINA1 gene, the function of the AAT protein is more or less impaired, ranging from mild to complete absence. In some mutations, e.g., In the case of the frequently occurring Z mutation, the molecule accumulates in the liver, leading to a deficiency of AAT throughout the body. This results in the protective function (enzymatic breakdown of lung tissue) being impaired or completely lost. This can lead to dysfunction of various organs, particularly the liver and lungs. AAT allele variants are classified into groups: Normal (Pi*M allele) = normal serum AAT level, Deficiency = significant reduction in serum AAT level, Null (Q0) = no detectable AAT. The different mutations are designated with letters from AZ and Null (Q0) and correspond to the migration rate during pH-dependent electrophoretic separation of the alpha-1 protein. The normal (healthy) allele is designated M. (Fig. 1). Since the human genome consists of a double set of chromosomes, the formula Pi*MM denotes a healthy person without the mutation (Pi stands for protease inhibitor, and the two following capital letters indicate the state of the two alleles). A distinction is made between homozygous, heterozygous, and compound heterozygous forms. Homozygous means that both alleles are identical; in the case of a disease, both alleles carry the same disease-causing mutation (e.g., Pi*ZZ). In the heterozygous form, only one gene copy (allele) is affected by the mutation, while the other remains unchanged (e.g., Pi*MZ). In the compound heterozygous mutation, two different mutations are present on both alleles (e.g., Pi*SZ). Most rare mutations have a name in addition to the letter, which is based on the patient's place of birth or the location or institution where the mutation was first discovered, e.g., Pi*M_Würzburg, Pi*L_Offenbach, Pi*Y_Barcelona, Pi*Q0_Matthew. There are some very rare mutations that have only been detected once so far. For some of these mutations, no name has been assigned; only the exact location of the mutation on the gene is given, e.g., c221T > A.

Little is still known about the epidemiology of rare AAT variants. The results from the Marburg Alpha-1 laboratory show rare variants in only 1 of the % samples submitted, suggesting a very rare occurrence in the population (Fig. 2Accurate diagnostics are crucial for detecting rare and previously undescribed mutations. Various analyses are available for this purpose, including determining serum AAT levels, genotyping (at the DNA level, screening for the 14 most common and rare AAT mutations), phenotyping (at the protein level), and, if necessary, sequencing (at the DNA level, complete coding region). Serum AAT levels are essential for detecting rare mutations and are also very important for the clinical evaluation of the detected mutations. In most cases, rare mutations can only be discovered by evaluating these various methods. Due to the very small number of patients, the clinical course of rare AAT mutations is difficult to assess. Questionnaire surveys are currently being conducted to gain a better understanding of this. For many rare mutations, no definitive statement can be made regarding the clinical presentation due to a lack of comparability. In the case of a rare disease like alpha-1 antirypsin deficiency, it is crucial to pool expert knowledge to facilitate comparison and exchange. One of the most important goals of current research is therefore to identify commonalities in order to understand the different disease courses despite identical mutations and to develop more targeted treatments.

By participating in the questionnaire, patients can actively contribute to research and a better understanding of the disease, which in turn benefits those affected.