Brief Communication
Alpha-1 antitrypsin deficiency caused by a novel mutation (p.Leu263Pro): Pi*ZQ0gaia – Q0gaia allele
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Matos, F. Fradinho, A. Catarino, P. Lopes, M.J. Matos" "autores" => array:5 [ 0 => array:2 [ "nombre" => "P." "apellidos" => "Matos" ] 1 => array:2 [ "nombre" => "F." "apellidos" => "Fradinho" ] 2 => array:2 [ "nombre" => "A." "apellidos" => "Catarino" ] 3 => array:2 [ "nombre" => "P." "apellidos" => "Lopes" ] 4 => array:2 [ "nombre" => "M.J." "apellidos" => "Matos" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173511515001372?idApp=UINPBA00004E" "url" => "/21735115/0000002100000006/v4_201605090016/S2173511515001372/v4_201605090016/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S2173511515000834" "issn" => "21735115" "doi" => "10.1016/j.rppnen.2015.03.005" "estado" => "S300" "fechaPublicacion" => "2015-11-01" "aid" => "1056" "copyright" => "Sociedade Portuguesa de Pneumologia" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Pneumol. 2015;21:334-40" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 1465 "formatos" => array:3 [ "EPUB" => 214 "HTML" => 730 "PDF" => 521 ] ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Special Article</span>" "titulo" => "Multidisciplinary rehabilitation in ventilator-dependent patients: Call for action in specialized inpatient facilities" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => "en" "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "334" "paginaFinal" => "340" ] ] "contieneResumen" => array:1 [ "en" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1735 "Ancho" => 975 "Tamanyo" => 240948 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">A ventilator-dependent tracheostomized patient walking with assistance from the staff.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "J. Winck, R. Camacho, N. Ambrosino" "autores" => array:3 [ 0 => array:2 [ "nombre" => "J." "apellidos" => "Winck" ] 1 => array:2 [ "nombre" => "R." "apellidos" => "Camacho" ] 2 => array:2 [ "nombre" => "N." "apellidos" => "Ambrosino" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S2173511515000834?idApp=UINPBA00004E" "url" => "/21735115/0000002100000006/v4_201605090016/S2173511515000834/v4_201605090016/en/main.assets" ] "en" => array:18 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Brief Communication</span>" "titulo" => "Alpha-1 antitrypsin deficiency caused by a novel mutation (p.Leu263Pro): Pi*ZQ0gaia – Q0gaia allele" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "341" "paginaFinal" => "343" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "M.J. Oliveira, S. Seixas, I. Ladeira, R. Monteiro, T. Shiang, M. Guimarães, R. Lima" "autores" => array:7 [ 0 => array:4 [ "nombre" => "M.J." "apellidos" => "Oliveira" "email" => array:1 [ 0 => "maria.joaooliveira@chvng.min-saude.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "S." "apellidos" => "Seixas" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] 2 => array:3 [ "nombre" => "I." "apellidos" => "Ladeira" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 3 => array:3 [ "nombre" => "R." "apellidos" => "Monteiro" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 4 => array:3 [ "nombre" => "T." "apellidos" => "Shiang" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 5 => array:3 [ "nombre" => "M." "apellidos" => "Guimarães" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 6 => array:3 [ "nombre" => "R." "apellidos" => "Lima" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Department of Pulmonology, Centro Hospitalar de Vila Nova de Gaia/Espinho, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Investigação e Inovação em Saúde (I3S), University of Porto, Portugal" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Institute of Molecular Pathology and Immunology (IPATIMUP), University of Porto, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1068 "Ancho" => 1555 "Tamanyo" => 83683 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263.</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Human alpha-1 antitrypsin (AAT), also called proteinase inhibitor (PI), belongs to the serine protease inhibitors superfamily (SERPIN) and is a mature glycoprotein; it is composed of a single chain of 394 amino acids, and three side chains of carbohydrates, weighting approximately 52<span class="elsevierStyleHsp" style=""></span>kDa. AAT is also the major SERPIN in the serum and a water soluble molecule with a half-life of 4–5 days, encoded by <span class="elsevierStyleItalic">SERPINA1</span> gene located on chromosome 14.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">1</span></a> More than 80% of AAT is synthesized and secreted by hepatocytes, with humans producing about 34<span class="elsevierStyleHsp" style=""></span>mg/kg/day, which results in serum concentrations of 1–2<span class="elsevierStyleHsp" style=""></span>g/L. Approximately, 80% diffuses from serum into interstitial tissues and 0.5–10% reaches other biological fluids like alveolar fluid, saliva, tears, milk, semen, bile and urine.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">2–4</span></a><span class="elsevierStyleItalic">SERPINA1</span> has numerous gene variants among common and rare alleles, and normal, deficiency and null variants, which determine protein serum levels in an autosomal codominant mode. Severe AAT deficiency (AATD) is probably one of the most common hereditary conditions, estimated to affect between 70,000 and 100,000 individuals in Europe and defined by serum AAT levels below 35% of the expected value (50<span class="elsevierStyleHsp" style=""></span>mg/dL and 11<span class="elsevierStyleHsp" style=""></span>mmol/L or 80<span class="elsevierStyleHsp" style=""></span>mg/dL, as measured by nephelometry and radial immunodiffusion, respectively).<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">5</span></a> DAAT is generally associated with PI*ZZ genotype and less often with combinations of PI*Z, PI*S, and other rarer deficiency or null (Q0) alleles.<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">3,4,6</span></a> Severe AATD predisposes patients to various diseases, including pulmonary emphysema, liver disease, systemic vasculitis and panniculitis. In Portugal the incidence of chronic obstructive pulmonary disease (COPD) is 14.2% in patients over 40 years old,<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">7</span></a> and even though the prevalence of AATD in COPD patients is not well established, it is estimated to be about 1–3%.<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">3</span></a> Pulmonary emphysema associated with AATD is characterized by early onset (between 35 and 45 years), which is usually accelerated by patient smoking history.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Case report</span><p id="par0010" class="elsevierStylePara elsevierViewall">We present a case of a 41 year old man, former smoker (18 PPY), who was referred to our pulmonology outpatient clinic in 2009, due to COPD. He had dyspnea (mMRC 2) and was treated with tiotropium bromide, formoterol, budesonide and aminophylline. The initial physical examination showed a lung auscultation with decrease breath sounds and no other significant changes. Additional exams revealed an already compromised respiratory function with very severe obstruction (FEV<span class="elsevierStyleInf">1</span>/FVC 41%, FEV<span class="elsevierStyleInf">1</span> 31% (1130<span class="elsevierStyleHsp" style=""></span>ml) and FVC 70%); arterial blood gas with hypoxemia (PaO2 65<span class="elsevierStyleHsp" style=""></span>mmHg) and normocapnia (35<span class="elsevierStyleHsp" style=""></span>mmHg). Furthermore, the study of alveolar capillary diffusion of carbon monoxide (DLCO) was moderately reduced (45%); chest computed tomography (CT) confirmed severe symptoms of diffuse emphysema; and AAT serum concentration was 22.2<span class="elsevierStyleHsp" style=""></span>mg/dl. Later, the evaluation of patient genotype showed incongruent results between protein electrophoresis (immunoelectrophoresis, pH 4.46 and 4.96) and protein chain reaction (PCR) multiplex screening of PI*Z and PI*S mutation,<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">8,9</span></a> a Z phenotype versus MZ genotype. This was explained by a novel mutation c.860T>C/p.(Leu263Pro) in exon III of <span class="elsevierStyleItalic">SERPINA1</span> (genomic reference <a id="intr0005" class="elsevierStyleInterRef" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=nucleotide&doptcmdl=genbank&term=NM_000295.4">NM_000295.4</a>; for consistency with SERPINA1 literature the amino acid was numbered according to mature protein, 24 residues less UniProtKB: <a id="intr0010" class="elsevierStyleInterRef" href="uniprotkb:P01009">P01009</a>), predicted by different bioinformatic tools to have damaging effects in protein structure and to be a likely disease causing mutation (scores: Polyphen-2<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>1.0, SIFT<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0, PROVEAN<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−5.365 and Mutation Taster<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.99)<a class="elsevierStyleCrossRefs" href="#bib0115"><span class="elsevierStyleSup">10–12</span></a> and identified only after <span class="elsevierStyleItalic">SERPINA1</span> sequencing.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">8</span></a> The p.Leu263Pro mutation is located in a highly conserved residue among SERPINA1 orthologs (placental mammals) and in the vicinity of p.Glu264Val (c.863A>T) variant, underlying the common deficiency S allele. Likewise, the substitution of p.Leu263Pro is likely to cause a distortion of the α-helix G and affect SERPINA1 gate structural domain. Regarding these findings, the absence of a corresponding band in protein gel electrophoresis and the patient birth place, this allele was named Q0gaia (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Upon the diagnosis of pulmonary disease by AATD (COPD with severe airway obstruction), in a multidisciplinary meeting the patient was proposed for AAT replacement therapy. Despite the understanding of his clinical situation and the benefit he would have gained with the treatment, the patient delayed starting, due to the lack of availability for regular hospital visits. Over the past five years, the patient remained in follow-up and is currently proposed for AAT replacement therapy (60<span class="elsevierStyleHsp" style=""></span>mg/kg/week). Family screening was carried out, which identified the ZQ0 genotype in the patient's sister (a former smoker, who has FEV<span class="elsevierStyleInf">1</span> of 82%, mild reduced DLCO and no emphysema on CT chest scan).</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Discussion</span><p id="par0015" class="elsevierStylePara elsevierViewall">In this case report, COPD should probably be attributed to AATD owing to a reduced protection of the lung tissue against the neutrophil elastase, which leads to a progressive destruction of the parenchyma, and emphysema. Specifically, the increased risk of serious illness was caused by two alleles, both associated to severe AATD: PI*Z, a dysfunctional allele characterized by low secretion of AAT and an extremely rare variant Q0gaia (p.Leu263Pro) associated with very low or missing serum concentrations of AAT. Indeed, several examples from the literature show that Leu-Pro and Pro-Leu substitutions are linked to serious distortions in SERPIN structure. This is the case of SERPINA1 alleles Mprocida (p.Leu41Pro) and Mheerlen (p.Pro369Leu), which cause the distortions in A α-helix and in 1C-4B β-sheet strands, respectively, and are linked to dramatic reductions in serum levels (less than 95%), due to intracellular protein degradation.<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">13</span></a> Here, the biochemical properties of the leucine and proline residues may correlate to mutation pathogenesis, while leucine is a hydrophobic residue displaying a preference for α-helices, the proline is a small amino acid with unique properties, able to introduce kinks in protein structure. In addition, the severe lung disease was presented in a young patient with a former history of smoking. This case report aims to demonstrate not only a novel null allele underlying AATD and its associated disease risk, but also the challenge that AAT replacement therapy may represent to the life of a patient, who takes the decision not to be treated.</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Ethical disclosures</span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Protection of human and animal subjects</span><p id="par0020" class="elsevierStylePara elsevierViewall">The authors declare that no experiments were performed on humans or animals for this study.</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Confidentiality of data</span><p id="par0025" class="elsevierStylePara elsevierViewall">The authors declare that they have followed the protocols of their work center on the publication of patient data.</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Right to privacy and informed consent</span><p id="par0030" class="elsevierStylePara elsevierViewall">The authors have obtained the written informed consent of the patients or subjects mentioned in the article. The corresponding author is in possession of this document.</p></span></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Conflicts of interest</span><p id="par0035" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:8 [ 0 => array:3 [ "identificador" => "xres634662" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec647191" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 3 => array:2 [ "identificador" => "sec0010" "titulo" => "Case report" ] 4 => array:2 [ "identificador" => "sec0015" "titulo" => "Discussion" ] 5 => array:3 [ "identificador" => "sec0020" "titulo" => "Ethical disclosures" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0025" "titulo" => "Protection of human and animal subjects" ] 1 => array:2 [ "identificador" => "sec0030" "titulo" => "Confidentiality of data" ] 2 => array:2 [ "identificador" => "sec0035" "titulo" => "Right to privacy and informed consent" ] ] ] 6 => array:2 [ "identificador" => "sec0040" "titulo" => "Conflicts of interest" ] 7 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2015-05-18" "fechaAceptado" => "2015-07-08" "PalabrasClave" => array:1 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec647191" "palabras" => array:3 [ 0 => "Alpha-1 antitrypsin deficiency" 1 => "Null allele" 2 => "COPD" ] ] ] ] "tieneResumen" => true "resumen" => array:1 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Severe alpha-1 antitrypsin deficiency (AATD) is generally associated with PI*ZZ genotype and less often with combinations of PI*Z, PI*S, and other rarer deficiency or null (Q0) alleles. Severe AATD predisposes patients to various diseases, including pulmonary emphysema. Presented here is a case report of a young man with COPD and AATD. The investigation of the AATD showed a novel mutation p.Leu263Pro (c.860T>C), which was named Q0gaia (Pi*ZQ0gaia). Q0gaia is associated with very low or no detectable serum concentrations of AAT.</p></span>" ] ] "multimedia" => array:1 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1068 "Ancho" => 1555 "Tamanyo" => 83683 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Characterization of Q0Gaia allele. (A) Protein gel electrophoresis. Index case ZQ0 displays only a band corresponding to PI*Z allele. (B) Electropherogram of the index case. The arrow shows the region of the T to C mutation in codon 263.</p>" ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:13 [ 0 => array:3 [ "identificador" => "bib0070" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Alpha-1 antitrypsin deficiency. The experience of Pulido Valente Hospital with augmentation therapy" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.A. Costa" 1 => "C. 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| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 5 | 8 | 13 |
| 2024 October | 22 | 36 | 58 |
| 2024 September | 38 | 30 | 68 |
| 2024 August | 56 | 37 | 93 |
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| 2024 May | 46 | 34 | 80 |
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| 2024 February | 25 | 23 | 48 |
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| 2023 November | 30 | 40 | 70 |
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| 2023 September | 24 | 34 | 58 |
| 2023 August | 14 | 12 | 26 |
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