دورية أكاديمية
New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency
| العنوان: | New cis-Acting Variants in PI*S Background Produce Null Phenotypes Causing Alpha-1 Antitrypsin Deficiency |
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| المؤلفون: | Matamala, Nerea, Gomez-Mariano, Gema Maria, Perez, Jose Antonio, Baladron-Jimenez, Beatriz Isabel, Torres-Durán, María, Michel, Francisco Javier, Saez, Raquel, Hernández-Pérez, Jose María, Belmonte, Irene, Rodriguez-Frias, Francisco, Blanco, Ignacio, Strnad, Pavel, Janciauskiene, Sabina, Martinez-Delgado, Beatriz |
| المساهمون: | Instituto de Salud Carlos III, Deutsche Forschungsgemeinschaft (Alemania) |
| بيانات النشر: | American Thoracic Society (ATS) |
| سنة النشر: | 2020 |
| المجموعة: | REPISALUD (REPositorio Institucional en SALUD del Instituto de Salud Carlos III - ISCIII) |
| مصطلحات موضوعية: | Alpha-1 antitrypsin, SERPINA 1 genetic mutations, PI*S allele, Polymerization, Adult, Alleles, DNA Mutational Analysis, Female, Gene Frequency, Genotype, Humans, Male, Middle Aged, Mutation, Phenotype, alpha 1-Antitrypsin, alpha 1-Antitrypsin Deficiency |
| الوصف: | Alpha-1 antitrypsin deficiency (AATD) is an inherited condition characterized by reduced levels of serum AAT due to mutations in the SERPINA1 (Serpin family A member 1) gene. The Pi*S (Glu264Val) is one of the most frequent deficient alleles of AATD, showing high incidence in the Iberian Peninsula. Herein, we describe two new alleles carrying an S mutation but producing a null phenotype: QOVigo and QOAachen. The new alleles were identified by sequencing the SERPINA1 gene in three patients who had lower AAT serum levels than expected for the initial genotype. These alleles are the result of combined mutations in cis in a PI*S allele. Sequencing detected the S mutation in cis with Tyr138Cys (S+Tyr138Cys) in two patients, whereas a third one had the S mutation in cis with Pro391Thr variant (S+Pro391Thr). When expressed in a cellular model, these variants caused strong AAT polymerization and very low AAT secretion to almost undetectable levels. The isoelectric focusing method for plasma AAT phenotyping did not show AAT protein encoded by the novel mutant alleles, behaving as null. We called these alleles PI*S-plus because the S variant was phased with another variant conferring more aggressive characteristics to the allele. The current data demonstrate that the clinical variability observed in AATD can be explained by additional genetic variation, such as dual cis-acting variants in the SERPINA1 gene. The possible existence of other unrevealed variants combined in the PI*S alleles should be considered to improve the genetic diagnosis of the patients. ; Supported by Institute of Health Carlos III grant AESI PI17CIII/00042, and by Deutsche Forschungsgemeinschaft (DFG) grant STR 1095/6-1 (Heisenberg Professorship) (P.S.) and DFG consortium grant SFB/TRR57 “Liver fibrosis” (P.S.). ; Sí |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 1535-4989 |
| العلاقة: | https://doi.org/10.1165/rcmb.2020-0021OCTest; info:fis/Instituto de Salud Carlos III/Programa Estatal de Fomento de la Investigación Científica y Técnica de Excelencia/Subprograma Estatal de Generación de Conocimiento/PI17-ISCIII Modalidad Proyectos de Investigacion en Salud Intramurales. (2017)/PI17CIII/00042; Am J Respir Cell Mol Biol. 2020 Oct;63(4):444-451.; http://hdl.handle.net/20.500.12105/17264Test; American journal of respiratory cell and molecular biology |
| DOI: | 10.1165/rcmb.2020-0021OC |
| الإتاحة: | https://doi.org/20.500.12105/17264Test https://doi.org/10.1165/rcmb.2020-0021OCTest https://hdl.handle.net/20.500.12105/17264Test |
| حقوق: | http://creativecommons.org/licenses/by-nc-nd/4.0Test/ ; Attribution-NonCommercial-NoDerivatives 4.0 Internacional ; open access |
| رقم الانضمام: | edsbas.CA4340A1 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 15354989 |
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| DOI: | 10.1165/rcmb.2020-0021OC |