Scientific Letter
Alpha-1-Antitrypsin Deficiency Associated With Null Alleles
Déficit de alfa-1-antitripsina asociado a alelos nulos
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It is caused by the inheritance of 2 severe deficiency alleles in the SERPINA1 gene,<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> and a plasma concentration of alpha-1 antitrypsin (AAT) below 50<span class="elsevierStyleHsp" style=""></span>mg/dl is representative of a significant deficiency. Up to 95% of clinical cases related with AATD are associated with the PI*ZZ genotype, while the other 5% are associated with PI*SZ and PI*MZ genotypes or combinations of PI*S or PI*Z with other extremely rare deficiency or null alleles. These rare alleles account for 4.6% of the deleterious variants recorded in the Spanish Registry of Patients with AAT Deficiency, and null variants are very rare indeed.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">2</span></a> Although around 25 null variants have been discovered in the last 20 years or so, little information is available on their clinical impact.<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3–9</span></a> We report 2 cases of patients referred to the respiratory medicine clinic with a diagnosis of AATD associated with the PI*Q0amersfoort and PI*Q0cardiff allele.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first was a 47-year-old woman, native of the former republic of Yugoslavia, with a smoking history of 15 pack-years, referred to the respiratory medicine clinic for a 1-year history of dyspnea on moderate exertion (mMRC 2). Lung function tests results were as follows: FEV1/FVC 0.5; FEV1 1.80<span class="elsevierStyleHsp" style=""></span>l (55%); FVC 3.40<span class="elsevierStyleHsp" style=""></span>l (77%); DLCO 53%; KCO 52%. High-resolution computed tomography revealed centrilobular emphysema, predominantly in both lower lobes. Complete blood count, IgA, IgM, IgG, IgE and transaminases were within normal levels. Plasma AAT determined by nephelometry was 18<span class="elsevierStyleHsp" style=""></span>mg/dl, so a genetic study to detect deficiency alleles S and Z was performed using real-time PCR (FRET, LightCycler 2.0, and TIB MOLBIOL probes), which detected heterozygosity for the PI*Z allele, while the presence of PI*S alleles was ruled out. In view of the discordance between the genotype obtained and AAT plasma levels, a molecular study was performed of all exonic coding regions and of the intronic sequences flanking the SERPINA1 gene, using Sanger sequencing (BigDye™ Terminator v3.1 Cycle Sequencing, Thermo Fisher Scientific). In this study, in addition to the PI*Z described above, heterozygosity for the PI*Q0amersfoort allele was detected (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0015" class="elsevierStylePara elsevierViewall">The second case was a 42-year-old man with no clinical history of interest, who was referred to our clinic for a family history of AATD. He had severe AAT deficiency (41<span class="elsevierStyleHsp" style=""></span>mg/dl), and heterozygosity for the PI*Z allele was detected. Molecular study of the SERPINA1 gene revealed a Z/Q0cardiff genotype (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The patient had no respiratory symptoms or liver disease. Lung function test results were within normal limits: FEV1/FVC 0.79; FEV1 4.82<span class="elsevierStyleHsp" style=""></span>l (109%); FVC 5.60<span class="elsevierStyleHsp" style=""></span>l (112%); DLCO 109%; KCO 106%. Chest radiograph and general laboratory tests were unremarkable.</p><p id="par0020" class="elsevierStylePara elsevierViewall">AAT is an antiprotease, produced mainly by the hepatocytes, which inhibits the elastase activity of the neutrophils. Normal plasma levels range between 120 and 200<span class="elsevierStyleHsp" style=""></span>mg/dl.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Although the Z mutation (p.Glu 342 Lys) deficiency allele is the most common and leads to very low AAT levels in plasma (around 10%–15% of the normal level), serum AAT levels in null mutations are extremely low or undetectable<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3–9</span></a>: a wide range of molecular mechanisms are involved in this outcome, including errors in protein synthesis or post-translational degradation.<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6,10–12</span></a> For this reason, genotypes consisting of null homozygotes or accompanied by other deficiency alleles of the SERPINA1 gene carry a particularly high risk of very early onset pulmonary emphysema, even earlier than would be expected in the ZZ genotype.<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">With regard to PI*Q0amersfoort, the limited literature available suggests that both heterozygous and homozygous forms lead to COPD at an early age, as observed in our female patient, with no liver involvement whatsoever.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7,8</span></a> This mutation causes a stop codon at position 184 of the protein, resulting in a severe deficiency when associated with other deficiency variants, such as PI*Z. Like other null alleles, the PI*Q0amersfoort variant does not cause liver disease because the protein is not polymerized in the liver, as occurs in mutations caused by amino acid switches, in which deficiencies exist that alter protein structure and folding, giving rise to accumulation in the endoplasmic reticulum of the hepatocytes, resulting ultimately in tissue damage.</p><p id="par0030" class="elsevierStylePara elsevierViewall">In the case of PI*Q0cardiff, the amino acid aspartate is replaced by valine at position 256 of the ATT protein. This substitution causes a severe deficiency when it occurs in homozygosis or in association with other deficiency variants such as PI*Z. Some authors argue that homozygous Q0cardiff patients are not at risk for emphysema, although there may be a risk if it occurs in heterozygosity with the PI*Z allele or other null alleles.<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">9,14</span></a> In our case, the male patient was asymptomatic. In our opinion, PI*Q0cardiff cannot be considered a null allele, since it is not a mutation that causes a premature stop codon, nor does it produce complete protein degradation, a mechanism usually observed in null deficiency alleles.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> Some authors define the PI*Q0cardiff variant as PI*P(lowell), since the genetic variation consisting of the switch of an aspartic acid to valine<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">9</span></a> causes degradation of the intracellular protein, which leads to reduced, but not undetectable, levels of protein.<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> It seems likely that these residual protein levels, along with those produced by the PI*Z allele, caused our patient to present AAT levels higher than those found in patients with null alleles.</p></span>" "pdfFichero" => "main.pdf" "tienePdf" => true "NotaPie" => array:1 [ 0 => array:2 [ "etiqueta" => "☆" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as: Figueira Gonçalves JM, Martínez Bugallo F, García-Talavera I, Rodríguez González J. Déficit de alfa-1-antitripsina asociado a alelos nulos. Arch Bronconeumol. 2017;53:700–702.</p>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 2116 "Ancho" => 2667 "Tamanyo" => 592071 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Identification of PI*Q0Amersfoort and PI*Q0cardiff null alleles.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:15 [ 0 => array:3 [ "identificador" => "bib0080" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:3 [ "comentario" => "No authors listed" "contribucion" => array:1 [ 0 => array:1 [ "titulo" => "American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency" ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1164/rccm.168.7.818" "Revista" => array:6 [ "tituloSerie" => "Am J Respir Crit Care Med" "fecha" => "2003" "volumen" => "168" "paginaInicial" => "818" "paginaFinal" => "900" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14522813" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0085" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Spanish Registry of Patients With Alpha-1 Antitrypsin Deficiency: database evaluation and population analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "B. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 4 | 2 | 6 |
| 2024 October | 102 | 22 | 124 |
| 2024 September | 97 | 15 | 112 |
| 2024 August | 105 | 44 | 149 |
| 2024 July | 100 | 25 | 125 |
| 2024 June | 146 | 28 | 174 |
| 2024 May | 115 | 31 | 146 |
| 2024 April | 66 | 40 | 106 |
| 2024 March | 74 | 28 | 102 |
| 2024 February | 63 | 23 | 86 |
| 2023 August | 1 | 0 | 1 |
| 2023 March | 8 | 4 | 12 |
| 2023 February | 81 | 26 | 107 |
| 2023 January | 68 | 35 | 103 |
| 2022 December | 98 | 45 | 143 |
| 2022 November | 82 | 35 | 117 |
| 2022 October | 91 | 47 | 138 |
| 2022 September | 61 | 37 | 98 |
| 2022 August | 64 | 41 | 105 |
| 2022 July | 74 | 52 | 126 |
| 2022 June | 82 | 59 | 141 |
| 2022 May | 84 | 40 | 124 |
| 2022 April | 129 | 41 | 170 |
| 2022 March | 128 | 48 | 176 |
| 2022 February | 133 | 38 | 171 |
| 2022 January | 112 | 64 | 176 |
| 2021 December | 68 | 56 | 124 |
| 2021 November | 86 | 48 | 134 |
| 2021 October | 73 | 52 | 125 |
| 2021 September | 49 | 51 | 100 |
| 2021 August | 46 | 59 | 105 |
| 2021 July | 52 | 41 | 93 |
| 2021 June | 64 | 49 | 113 |
| 2021 May | 67 | 47 | 114 |
| 2021 April | 231 | 122 | 353 |
| 2021 March | 195 | 36 | 231 |
| 2021 February | 189 | 32 | 221 |
| 2021 January | 67 | 20 | 87 |
| 2020 December | 69 | 21 | 90 |
| 2020 November | 103 | 15 | 118 |
| 2020 October | 109 | 21 | 130 |
| 2020 September | 66 | 26 | 92 |
| 2020 August | 78 | 14 | 92 |
| 2020 July | 83 | 23 | 106 |
| 2020 June | 60 | 14 | 74 |
| 2020 May | 65 | 14 | 79 |
| 2020 April | 73 | 23 | 96 |
| 2020 March | 87 | 14 | 101 |
| 2020 February | 88 | 19 | 107 |
| 2020 January | 110 | 30 | 140 |
| 2019 December | 89 | 14 | 103 |
| 2019 November | 64 | 26 | 90 |
| 2019 October | 65 | 10 | 75 |
| 2019 September | 81 | 16 | 97 |
| 2019 August | 78 | 17 | 95 |
| 2019 July | 43 | 22 | 65 |
| 2019 June | 51 | 24 | 75 |
| 2019 May | 73 | 21 | 94 |
| 2019 April | 85 | 32 | 117 |
| 2019 March | 66 | 26 | 92 |
| 2019 February | 56 | 24 | 80 |
| 2019 January | 43 | 37 | 80 |
| 2018 December | 54 | 31 | 85 |
| 2018 November | 89 | 24 | 113 |
| 2018 October | 164 | 29 | 193 |
| 2018 September | 62 | 8 | 70 |
| 2018 May | 4 | 0 | 4 |
| 2018 April | 71 | 10 | 81 |
| 2018 March | 59 | 18 | 77 |
| 2018 January | 1 | 0 | 1 |
| 2017 November | 0 | 1 | 1 |
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