The Z (c.1096G > A; p.Glu366Lys) and S (c.863A > T; p.Glu288Val) deficiency variants are the most frequently found variants in AATD, with the Z variant present in most individuals diagnosed with AATD. However, there are many other less frequent variants known to contribute to lung and/or liver disease in AATD. To identify the most common rare variants associated with AATD, we conducted a systematic literature review with the aim of assessing AATD variation patterns across the world.
Of the 4945 articles identified by the search string, 864 contained useful information for this study. Most articles came from the United States, followed by the United Kingdom, Germany, Spain, and Italy. Collectively, the articles identified a total of 7631 rare variants and 216 types of rare variant across 80 counties. The F (c.739C > T; p.Arg247Cys) variant was identified 1,281 times and was the most reported known rare variant worldwide, followed by the I (c.187C > T; p.Arg63Cys) variant. Worldwide, there were 1492 Null/rare variants that were unidentified at the time of source article publication and 75 rare novel variants reported only once.
Rare variants in alpha 1 antitrypsin deficiency: a systematic literature review - U.S. National Institute of Health
The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AATalpha-1 antitrypsin More, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AATalpha-1 antitrypsin More reactive loop and through effects on core packing. In conclusion, the new AATalpha-1 antitrypsin More deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant.
The combination of the M allele with any deficient or null allele (Z, Mprocida, Mpalermo, Mheerlen, and the newly identified Q0soest and Q0amersfoort alleles) produces mild to intermediate α1AT deficiencies, with concentrations of 0.64–1.3 g/L. Such allele combinations may have importance, however, because Dahl et al. has demonstrated that the presence of an intermediate α1AT deficiency will not affect lung function in the average individual but may produce marked aggravation of airway obstruction in individuals prone to develop COPD.
Inherited ChronicA condition or illness that arises slowly over days or weeks and may or may not resolve with treatment. It is the opposite of acute. More Obstructive PulmonaryMedical term referring to the lungs. More Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles - Clinical Chemistry
Apart from the most frequent deficiency alleles, Pi S and Pi Z, some A1AT alleles of clinical significance may be easily misdiagnosed. This is typically the case of the Pi Mmalton variant which shares the same ‘gain-of-function’ liver toxicity than Pi Z and the same ‘loss of function’ lung disease as well.
The MMalton and MPalermo are two rare variants characterized by a p.Phe52del (c.226_228delTTC) mutation linked to either a M2 or M1Val213 allele, respectively. Importantly, this mutation previously described as increasing the risk of hepatic disease even when in heterozygosity with non-deficiency alleles was found to be the most widespread in Portugal
Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal - Science Direct
The MMalton and MPalermo are two rare variants characterized by a p.Phe52del (c.226_228delTTC) mutation linked to either a M2 or M1Val213 allele, respectively. Importantly, this mutation previously described as increasing the risk of hepatic disease even when in heterozygosity with non-deficiency alleles was found to be the most widespread in Portugal
Alpha-1-antitrypsin (SERPINA1) mutation spectrum: Three novel variants and haplotype characterization of rare deficiency alleles identified in Portugal - Science Direct
Epidemiology of rare (non-Z, non-S) AATalpha-1 antitrypsin More deficient variants
Little is known about the genetic epidemiology of rare AATalpha-1 antitrypsin More deficient variants which are considered not to exceed 2–4% of all variants. However, the prevalence of these variants may be higher than was previously believed because rare AATalpha-1 antitrypsin More deficient variants can be mistaken for the PI*Z variant and therefore misdiagnosed. Indeed, we have preliminary data from the Italian Registry for AATalpha-1 antitrypsin More Deficiency to indicate that as many as 22% of the total AATalpha-1 antitrypsin More deficient variants are rare. The nomenclature of some of these variants (see above) reflects their probable Italian origin (Mprocida, Mpalermo, QOisola di procida, QOtrastevere). An intriguing question is: are the rare AATalpha-1 antitrypsin More deficient variants more frequent in those countries in which the gene frequency of PiZ is lower? Data from the island of Sardinia seem to support this hypothesis. Clinical phenotypes associated with the common AATalpha-1 antitrypsin More deficient variant PI*Z are reasonably well defined, as will be discussed later in this review series, but no information is so far available on clinical phenotypes associated with rare AATalpha-1 antitrypsin More deficient variants. This should be addressed by future studies.α1-Antitrypsin deficiency · 1: Epidemiology of α1-antitrypsin deficiency - BMJ Journals
The combination of the M allele with any deficient or null allele (Z, Mprocida, Mpalermo, Mheerlen, and the newly identified Q0soest and Q0amersfoort alleles) produces mild to intermediate α1AT deficiencies, with concentrations of 0.64–1.3 g/L. Such allele combinations may have importance, however, because Dahl et al. has demonstrated that the presence of an intermediate α1AT deficiency will not affect lung function in the average individual but may produce marked aggravation of airway obstruction in individuals prone to develop COPD.
Inherited ChronicA condition or illness that arises slowly over days or weeks and may or may not resolve with treatment. It is the opposite of acute. More Obstructive PulmonaryMedical term referring to the lungs. More Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles - Clinical Chemistry
The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AATalpha-1 antitrypsin More, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AATalpha-1 antitrypsin More reactive loop and through effects on core packing. In conclusion, the new AATalpha-1 antitrypsin More deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant.
There is a rare Alpha-1 abnormality, the Mpittsburgh phenotype, which leads to a normal level with coagulation problems. It can sometimes be confused with the M phenotype. If you were PiMpittsburghZ, this is a severely deficient phenotype and should be treated.
Alpha-1 Lung Disease Questions & Answers - Alpha-1 Foundation
Epidemiology of rare (non-Z, non-S) AATalpha-1 antitrypsin More deficient variants
Little is known about the genetic epidemiology of rare AATalpha-1 antitrypsin More deficient variants which are considered not to exceed 2–4% of all variants. However, the prevalence of these variants may be higher than was previously believed because rare AATalpha-1 antitrypsin More deficient variants can be mistaken for the PI*Z variant and therefore misdiagnosed. Indeed, we have preliminary data from the Italian Registry for AATalpha-1 antitrypsin More Deficiency to indicate that as many as 22% of the total AATalpha-1 antitrypsin More deficient variants are rare. The nomenclature of some of these variants (see above) reflects their probable Italian origin (Mprocida, Mpalermo, QOisola di procida, QOtrastevere). An intriguing question is: are the rare AATalpha-1 antitrypsin More deficient variants more frequent in those countries in which the gene frequency of PiZ is lower? Data from the island of Sardinia seem to support this hypothesis. Clinical phenotypes associated with the common AATalpha-1 antitrypsin More deficient variant PI*Z are reasonably well defined, as will be discussed later in this review series, but no information is so far available on clinical phenotypes associated with rare AATalpha-1 antitrypsin More deficient variants. This should be addressed by future studies.α1-Antitrypsin deficiency · 1: Epidemiology of α1-antitrypsin deficiency - BMJ Journals
The "deficiency" group of alpha 1-antitrypsin (alpha 1AT) alleles is characterized by alpha 1AT genes that code for alpha 1AT present in serum but in amounts insufficient to protect the lower respiratory tract from progressive destruction by its burden of neutrophil elastaseA powerful enzyme released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin. Source: Genetics Home Reference. More. Mprocida, a rare alpha 1AT allele associated with alpha 1AT serum levels less than 10 mg/dl (normal 150-350 mg/dl), codes for an alpha 1AT molecule that focuses on immobilized pH gradient isoelectric gels slightly cathodal to the common normal M1 (Val213) protein. On a per molecule basis, Mprocida has a mildly reduced function as an inhibitor, with an association rate constant for human neutrophil elastaseA powerful enzyme released from white blood cells to fight infection, but it can attack normal tissues (especially the lungs) if not tightly controlled by alpha-1 antitrypsin. Source: Genetics Home Reference. More of 7.0 +/-0.1 x 10(6) M-1 s-1 (normal M1 (Val213) 9.3 +/-0.8 x 10(6), p less than 0.01). The Mprocida molecule behaves normally in vivo with a half-life similar to normal M1 alpha 1AT molecules. Restriction endonuclease mapping demonstrates that the cloned Mprocida gene was grossly intact. Sequencing of all the exons, exon-intron junctions, and the major promoter region demonstrated Mprocida to be identical to the M1 (Val213) gene except for a single base substitution in exon II coding for amino acid 41 of the mature protein (M1 (Val213) Leu41 CTG----Mprocida Pro41 CCG). Usefully, the coding sequence of the alpha 1AT residues 40-41 is recognized by the restriction endonuclease PvuII so that using a probe corresponding to this region of exon II, the Mprocida mutation can be rapidly identified by Southern analysis. Evaluation of the crystallographic structure of alpha 1AT suggests the Leu41 to Pro41 mutation may disrupt alpha-helix A in the region of Pro21-Ser45, suggesting the possibility that the alpha 1AT Mprocida molecule is unstable and degraded intracellularly prior to secretion.
The combination of the M allele with any deficient or null allele (Z, Mprocida, Mpalermo, Mheerlen, and the newly identified Q0soest and Q0amersfoort alleles) produces mild to intermediate α1AT deficiencies, with concentrations of 0.64–1.3 g/L. Such allele combinations may have importance, however, because Dahl et al. has demonstrated that the presence of an intermediate α1AT deficiency will not affect lung function in the average individual but may produce marked aggravation of airway obstruction in individuals prone to develop COPD.
Inherited ChronicA condition or illness that arises slowly over days or weeks and may or may not resolve with treatment. It is the opposite of acute. More Obstructive PulmonaryMedical term referring to the lungs. More Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles - Clinical Chemistry
Epidemiology of rare (non-Z, non-S) AATalpha-1 antitrypsin More deficient variants
Little is known about the genetic epidemiology of rare AATalpha-1 antitrypsin More deficient variants which are considered not to exceed 2–4% of all variants. However, the prevalence of these variants may be higher than was previously believed because rare AATalpha-1 antitrypsin More deficient variants can be mistaken for the PI*Z variant and therefore misdiagnosed. Indeed, we have preliminary data from the Italian Registry for AATalpha-1 antitrypsin More Deficiency to indicate that as many as 22% of the total AATalpha-1 antitrypsin More deficient variants are rare. The nomenclature of some of these variants (see above) reflects their probable Italian origin (Mprocida, Mpalermo, QOisola di procida, QOtrastevere). An intriguing question is: are the rare AATalpha-1 antitrypsin More deficient variants more frequent in those countries in which the gene frequency of PiZ is lower? Data from the island of Sardinia seem to support this hypothesis. Clinical phenotypes associated with the common AATalpha-1 antitrypsin More deficient variant PI*Z are reasonably well defined, as will be discussed later in this review series, but no information is so far available on clinical phenotypes associated with rare AATalpha-1 antitrypsin More deficient variants. This should be addressed by future studies.α1-Antitrypsin deficiency · 1: Epidemiology of α1-antitrypsin deficiency - BMJ Journals
The combination of the M allele with any deficient or null allele (Z, Mprocida, Mpalermo, Mheerlen, and the newly identified Q0soest and Q0amersfoort alleles) produces mild to intermediate α1AT deficiencies, with concentrations of 0.64–1.3 g/L. Such allele combinations may have importance, however, because Dahl et al. has demonstrated that the presence of an intermediate α1AT deficiency will not affect lung function in the average individual but may produce marked aggravation of airway obstruction in individuals prone to develop COPD.
Inherited ChronicA condition or illness that arises slowly over days or weeks and may or may not resolve with treatment. It is the opposite of acute. More Obstructive PulmonaryMedical term referring to the lungs. More Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles - Clinical Chemistry
Epidemiology of rare (non-Z, non-S) AATalpha-1 antitrypsin More deficient variants
Little is known about the genetic epidemiology of rare AATalpha-1 antitrypsin More deficient variants which are considered not to exceed 2–4% of all variants. However, the prevalence of these variants may be higher than was previously believed because rare AATalpha-1 antitrypsin More deficient variants can be mistaken for the PI*Z variant and therefore misdiagnosed. Indeed, we have preliminary data from the Italian Registry for AATalpha-1 antitrypsin More Deficiency to indicate that as many as 22% of the total AATalpha-1 antitrypsin More deficient variants are rare. The nomenclature of some of these variants (see above) reflects their probable Italian origin (Mprocida, Mpalermo, QOisola di procida, QOtrastevere). An intriguing question is: are the rare AATalpha-1 antitrypsin More deficient variants more frequent in those countries in which the gene frequency of PiZ is lower? Data from the island of Sardinia seem to support this hypothesis. Clinical phenotypes associated with the common AATalpha-1 antitrypsin More deficient variant PI*Z are reasonably well defined, as will be discussed later in this review series, but no information is so far available on clinical phenotypes associated with rare AATalpha-1 antitrypsin More deficient variants. This should be addressed by future studies.α1-Antitrypsin deficiency · 1: Epidemiology of α1-antitrypsin deficiency - BMJ Journals
The combination of the M allele with any deficient or null allele (Z, Mprocida, Mpalermo, Mheerlen, and the newly identified Q0soest and Q0amersfoort alleles) produces mild to intermediate α1AT deficiencies, with concentrations of 0.64–1.3 g/L. Such allele combinations may have importance, however, because Dahl et al. has demonstrated that the presence of an intermediate α1AT deficiency will not affect lung function in the average individual but may produce marked aggravation of airway obstruction in individuals prone to develop COPD.
Inherited ChronicA condition or illness that arises slowly over days or weeks and may or may not resolve with treatment. It is the opposite of acute. More Obstructive PulmonaryMedical term referring to the lungs. More Disease: New Selective-Sequencing Workup for α1-Antitrypsin Deficiency Identifies 2 Previously Unidentified Null Alleles - Clinical Chemistry
The variants, called Mpisa (Lys259Ile), Etaurisano (Lys368Glu) and Yorzinuovi (Pro391His), showed reduced secretion compared to control M AATalpha-1 antitrypsin More, and accumulated to different extents in the cells as ordered polymeric structures resembling those formed by the Z variant. Structural analysis of the mutations showed that they may facilitate polymerization both by loosening ‘latch’ interactions constraining the AATalpha-1 antitrypsin More reactive loop and through effects on core packing. In conclusion, the new AATalpha-1 antitrypsin More deficiency variants, besides increasing the risk of lung disease, may predispose to liver disease, particularly if associated with the common Z variant.