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of the deleterious variants recorded in the Spanish Registry of Patients with AAT Deficiency&#44; and null variants are very rare indeed&#46;<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&#44; little information is available on their clinical impact&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;9</span></a> We report 2 cases of patients referred to the respiratory medicine clinic with a diagnosis of AATD associated with the PI&#42;Q0amersfoort and PI&#42;Q0cardiff allele&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first was a 47-year-old woman&#44; native of the former republic of Yugoslavia&#44; with a smoking history of 15 pack-years&#44; referred to the respiratory medicine clinic for a 1-year history of dyspnea on moderate exertion &#40;mMRC 2&#41;&#46; Lung function tests results were as follows&#58; FEV1&#47;FVC 0&#46;5&#59; FEV1 1&#46;80<span class="elsevierStyleHsp" style=""></span>l &#40;55&#37;&#41;&#59; FVC 3&#46;40<span class="elsevierStyleHsp" style=""></span>l &#40;77&#37;&#41;&#59; DLCO 53&#37;&#59; KCO 52&#37;&#46; High-resolution computed tomography revealed centrilobular emphysema&#44; predominantly in both lower lobes&#46; Complete blood count&#44; IgA&#44; IgM&#44; IgG&#44; IgE and transaminases were within normal levels&#46; Plasma AAT determined by nephelometry was 18<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; so a genetic study to detect deficiency alleles S and Z was performed using real-time PCR &#40;FRET&#44; LightCycler 2&#46;0&#44; and TIB MOLBIOL probes&#41;&#44; which detected heterozygosity for the PI&#42;Z allele&#44; while the presence of PI&#42;S alleles was ruled out&#46; In view of the discordance between the genotype obtained and AAT plasma levels&#44; a molecular study was performed of all exonic coding regions and of the intronic sequences flanking the SERPINA1 gene&#44; using Sanger sequencing &#40;BigDye&#8482; Terminator v3&#46;1 Cycle Sequencing&#44; Thermo Fisher Scientific&#41;&#46; In this study&#44; in addition to the PI&#42;Z described above&#44; heterozygosity for the PI&#42;Q0amersfoort allele was detected &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</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&#44; who was referred to our clinic for a family history of AATD&#46; He had severe AAT deficiency &#40;41<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#44; and heterozygosity for the PI&#42;Z allele was detected&#46; Molecular study of the SERPINA1 gene revealed a Z&#47;Q0cardiff genotype &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The patient had no respiratory symptoms or liver disease&#46; Lung function test results were within normal limits&#58; FEV1&#47;FVC 0&#46;79&#59; FEV1 4&#46;82<span class="elsevierStyleHsp" style=""></span>l &#40;109&#37;&#41;&#59; FVC 5&#46;60<span class="elsevierStyleHsp" style=""></span>l &#40;112&#37;&#41;&#59; DLCO 109&#37;&#59; KCO 106&#37;&#46; Chest radiograph and general laboratory tests were unremarkable&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">AAT is an antiprotease&#44; produced mainly by the hepatocytes&#44; which inhibits the elastase activity of the neutrophils&#46; Normal plasma levels range between 120 and 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Although the Z mutation &#40;p&#46;Glu 342 Lys&#41; deficiency allele is the most common and leads to very low AAT levels in plasma &#40;around 10&#37;&#8211;15&#37; of the normal level&#41;&#44; serum AAT levels in null mutations are extremely low or undetectable<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;9</span></a>&#58; a wide range of molecular mechanisms are involved in this outcome&#44; including errors in protein synthesis or post-translational degradation&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6&#44;10&#8211;12</span></a> For this reason&#44; 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&#44; even earlier than would be expected in the ZZ genotype&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">With regard to PI&#42;Q0amersfoort&#44; the limited literature available suggests that both heterozygous and homozygous forms lead to COPD at an early age&#44; as observed in our female patient&#44; with no liver involvement whatsoever&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7&#44;8</span></a> This mutation causes a stop codon at position 184 of the protein&#44; resulting in a severe deficiency when associated with other deficiency variants&#44; such as PI&#42;Z&#46; Like other null alleles&#44; the PI&#42;Q0amersfoort variant does not cause liver disease because the protein is not polymerized in the liver&#44; as occurs in mutations caused by amino acid switches&#44; in which deficiencies exist that alter protein structure and folding&#44; giving rise to accumulation in the endoplasmic reticulum of the hepatocytes&#44; resulting ultimately in tissue damage&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In the case of PI&#42;Q0cardiff&#44; the amino acid aspartate is replaced by valine at position 256 of the ATT protein&#46; This substitution causes a severe deficiency when it occurs in homozygosis or in association with other deficiency variants such as PI&#42;Z&#46; Some authors argue that homozygous Q0cardiff patients are not at risk for emphysema&#44; although there may be a risk if it occurs in heterozygosity with the PI&#42;Z allele or other null alleles&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">9&#44;14</span></a> In our case&#44; the male patient was asymptomatic&#46; In our opinion&#44; PI&#42;Q0cardiff cannot be considered a null allele&#44; since it is not a mutation that causes a premature stop codon&#44; nor does it produce complete protein degradation&#44; a mechanism usually observed in null deficiency alleles&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> Some authors define the PI&#42;Q0cardiff variant as PI&#42;P&#40;lowell&#41;&#44; 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&#44; which leads to reduced&#44; but not undetectable&#44; levels of protein&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> It seems likely that these residual protein levels&#44; along with those produced by the PI&#42;Z allele&#44; caused our patient to present AAT levels higher than those found in patients with null alleles&#46;</p></span>"
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Scientific Letter
Alpha-1-Antitrypsin Deficiency Associated With Null Alleles
Déficit de alfa-1-antitripsina asociado a alelos nulos
Juan Marco Figueira Gonçalvesa,
Corresponding author
juanmarcofigueira@gmail.com

Corresponding author.
, Francisco Martínez Bugallob, Ignacio García-Talaveraa, Jesús Rodríguez Gonzáleza
a Servicio de Neumología y Cirugía Torácica, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain
b Unidad de Genética, Servicio de Análisis Clínicos, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain
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of the deleterious variants recorded in the Spanish Registry of Patients with AAT Deficiency&#44; and null variants are very rare indeed&#46;<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&#44; little information is available on their clinical impact&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;9</span></a> We report 2 cases of patients referred to the respiratory medicine clinic with a diagnosis of AATD associated with the PI&#42;Q0amersfoort and PI&#42;Q0cardiff allele&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">The first was a 47-year-old woman&#44; native of the former republic of Yugoslavia&#44; with a smoking history of 15 pack-years&#44; referred to the respiratory medicine clinic for a 1-year history of dyspnea on moderate exertion &#40;mMRC 2&#41;&#46; Lung function tests results were as follows&#58; FEV1&#47;FVC 0&#46;5&#59; FEV1 1&#46;80<span class="elsevierStyleHsp" style=""></span>l &#40;55&#37;&#41;&#59; FVC 3&#46;40<span class="elsevierStyleHsp" style=""></span>l &#40;77&#37;&#41;&#59; DLCO 53&#37;&#59; KCO 52&#37;&#46; High-resolution computed tomography revealed centrilobular emphysema&#44; predominantly in both lower lobes&#46; Complete blood count&#44; IgA&#44; IgM&#44; IgG&#44; IgE and transaminases were within normal levels&#46; Plasma AAT determined by nephelometry was 18<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#44; so a genetic study to detect deficiency alleles S and Z was performed using real-time PCR &#40;FRET&#44; LightCycler 2&#46;0&#44; and TIB MOLBIOL probes&#41;&#44; which detected heterozygosity for the PI&#42;Z allele&#44; while the presence of PI&#42;S alleles was ruled out&#46; In view of the discordance between the genotype obtained and AAT plasma levels&#44; a molecular study was performed of all exonic coding regions and of the intronic sequences flanking the SERPINA1 gene&#44; using Sanger sequencing &#40;BigDye&#8482; Terminator v3&#46;1 Cycle Sequencing&#44; Thermo Fisher Scientific&#41;&#46; In this study&#44; in addition to the PI&#42;Z described above&#44; heterozygosity for the PI&#42;Q0amersfoort allele was detected &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</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&#44; who was referred to our clinic for a family history of AATD&#46; He had severe AAT deficiency &#40;41<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#41;&#44; and heterozygosity for the PI&#42;Z allele was detected&#46; Molecular study of the SERPINA1 gene revealed a Z&#47;Q0cardiff genotype &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The patient had no respiratory symptoms or liver disease&#46; Lung function test results were within normal limits&#58; FEV1&#47;FVC 0&#46;79&#59; FEV1 4&#46;82<span class="elsevierStyleHsp" style=""></span>l &#40;109&#37;&#41;&#59; FVC 5&#46;60<span class="elsevierStyleHsp" style=""></span>l &#40;112&#37;&#41;&#59; DLCO 109&#37;&#59; KCO 106&#37;&#46; Chest radiograph and general laboratory tests were unremarkable&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">AAT is an antiprotease&#44; produced mainly by the hepatocytes&#44; which inhibits the elastase activity of the neutrophils&#46; Normal plasma levels range between 120 and 200<span class="elsevierStyleHsp" style=""></span>mg&#47;dl&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">1</span></a> Although the Z mutation &#40;p&#46;Glu 342 Lys&#41; deficiency allele is the most common and leads to very low AAT levels in plasma &#40;around 10&#37;&#8211;15&#37; of the normal level&#41;&#44; serum AAT levels in null mutations are extremely low or undetectable<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">3&#8211;9</span></a>&#58; a wide range of molecular mechanisms are involved in this outcome&#44; including errors in protein synthesis or post-translational degradation&#46;<a class="elsevierStyleCrossRefs" href="#bib0105"><span class="elsevierStyleSup">6&#44;10&#8211;12</span></a> For this reason&#44; 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&#44; even earlier than would be expected in the ZZ genotype&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">13</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">With regard to PI&#42;Q0amersfoort&#44; the limited literature available suggests that both heterozygous and homozygous forms lead to COPD at an early age&#44; as observed in our female patient&#44; with no liver involvement whatsoever&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">7&#44;8</span></a> This mutation causes a stop codon at position 184 of the protein&#44; resulting in a severe deficiency when associated with other deficiency variants&#44; such as PI&#42;Z&#46; Like other null alleles&#44; the PI&#42;Q0amersfoort variant does not cause liver disease because the protein is not polymerized in the liver&#44; as occurs in mutations caused by amino acid switches&#44; in which deficiencies exist that alter protein structure and folding&#44; giving rise to accumulation in the endoplasmic reticulum of the hepatocytes&#44; resulting ultimately in tissue damage&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">In the case of PI&#42;Q0cardiff&#44; the amino acid aspartate is replaced by valine at position 256 of the ATT protein&#46; This substitution causes a severe deficiency when it occurs in homozygosis or in association with other deficiency variants such as PI&#42;Z&#46; Some authors argue that homozygous Q0cardiff patients are not at risk for emphysema&#44; although there may be a risk if it occurs in heterozygosity with the PI&#42;Z allele or other null alleles&#46;<a class="elsevierStyleCrossRefs" href="#bib0120"><span class="elsevierStyleSup">9&#44;14</span></a> In our case&#44; the male patient was asymptomatic&#46; In our opinion&#44; PI&#42;Q0cardiff cannot be considered a null allele&#44; since it is not a mutation that causes a premature stop codon&#44; nor does it produce complete protein degradation&#44; a mechanism usually observed in null deficiency alleles&#46;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">5</span></a> Some authors define the PI&#42;Q0cardiff variant as PI&#42;P&#40;lowell&#41;&#44; 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&#44; which leads to reduced&#44; but not undetectable&#44; levels of protein&#46;<a class="elsevierStyleCrossRef" href="#bib0150"><span class="elsevierStyleSup">15</span></a> It seems likely that these residual protein levels&#44; along with those produced by the PI&#42;Z allele&#44; caused our patient to present AAT levels higher than those found in patients with null alleles&#46;</p></span>"
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Article information
ISSN: 15792129
Original language: English
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