Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
Lara Gallego, Beatriz
Martínez, María Teresa
MetadataShow full item record
[Background]: Severe Alpha-1 Antitrypsin (AAT) deficiency is a hereditary condition caused by mutations in the SERPINA1 gene, which predisposes to lung emphysema and liver disease. It is usually related to PI*Z alleles, and less frequent to rare and null (QO) alleles. Null-AAT alleles represent the end of a continuum of variants associated with profound AAT deficiency and extremely increased risk of emphysema. [Methods]: A family with severe AAT deficiency was analyzed to achieve genetic diagnosis. The complete exons and introns of the SERPINA1 gene were sequenced and transcriptional analysis by RT-PCR was performed to characterize the effect of splicing variants found in the patients. In addition, a minigene MGserpa1_ex1b-1c was cloned into the pSAD vector to in vitro investigate the independent impact of variants on splicing process. [Results]: We report a new identified null allele (PI*QOMadrid) in two adult siblings with practically no detectable serum AAT. The PI*QOMadrid allele consist of a duplication of the thymine (T) in position +2 of the donor splice site of exon 1C (+2dupT). In these two subjects, PI*QOMadrid occurred in compound heterozygote combination with the previously described variant PI*QOPorto. Both QOMadrid and QOPorto variants are located very close together in a regulatory region of the SERPINA1 gene. Analysis of transcripts revealed that QOMadrid variant prevented the expression of transcripts from exon 1C, and then normally spliced RNA products are not expected in the liver of these patients. In addition, aberrant splicing patterns of both variants were clearly distinguished and quantified by functional in vitro assays lending further support to their pathogenicity. [Conclusion]: Finding pathogenic mutations in non-coding regions of the SERPINA1 highlight the importance that regulatory regions might have in the disease. Regulatory regions should be seriously considered in discordant cases with severe AAT deficiency where no coding mutations were found.
Is part ofRespiratory Research, 2014, vol. 15, art. 125
European research projects
Except where otherwise noted, this item's license is described as cc-by (c) Beatriz Lara et al., 2015
Showing items related by title, author, creator and subject.
Martí Fàbregas, Joan; Medrano-Martorell, Santiago; Merino, Elisa; Prats Sánchez, Luis; Marín, Rebeca; Delgado Mederos, Raquel; Camps Renom, Pol; Martínez Domeño, Alejandro; Gómez Choco, Manuel; Lara, Lidia; Casado-Naranjo, Ignacio; Cánovas, David; Torres, Maria José; Freijo, María del Mar; Calleja, Ana; Bravo, Yolanda; Cocho, Dolores; Rodríguez-Campello, Ana; Zandio, Beatriz; Fuentes, Blanca; Felipe, Alicia de; Llull, Laura; Maestre, José; Hernández, María; Garcés, Moisés; Arce-Borda, Ana Maria de; Palomeras, Ernest; Rodríguez-Yáñez, Manuel; Díaz-Maroto, Inma; Serrano, Marta; Fernández-Domínguez, Jéssica; Sanahuja Montesinos, Jordi; Purroy Garcia, Francisco; Zedde, Marialuisa; Delgado-Mengual, Jordi; Gich, Ignasi (Nature Publishing Group, 2018)We investigated whether pre-treatment with statins is associated with surrogate markers of amyloid and hypertensive angiopathies in patients who need to start long-term oral anticoagulation therapy. A prospective multicenter ...
The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors Landa, Iñigo; Ruiz-Llorente, Sergio; Montero-Conde, Cristina; Inglada-Pérez, Lucía; Schiavi, Francesca; Leskelä, Susanna; Pita, Guillermo; Milne, Roger; Maravall Royo, Javier; Ramos, Ignacio; Andía, Víctor; Rodríguez-Poyo, Paloma; Jara-Albarrán, Antonino; Meoro, Amparo; Peso, Cristina del; Arribas, Luis; Iglesias, Pedro; Caballero, Javier; Serrano, Joaquín; Picó, Antonio; Pomares, Francisco; Giménez, Gabriel; López-Mondéjar, Pedro; Castello, Roberto; Merante-Boschin, Isabella; Pelizzo, Maria-Rosa; Mauricio Puente, Dídac; Opocher, Giuseppe; Rodríguez-Antona, Cristina; González- Neira, Anna; Matias-Guiu, Xavier; Santisteban, Pilar; Robledo, Mercedes (Public Library of Science, 2009)In order to identify genetic factors related to thyroid cancer susceptibility, we adopted a candidate gene approach. We studied tag- and putative functional SNPs in genes involved in thyroid cell differentiation and ...
Genome-Wide Association Study of VKORC1 and CYP2C9 on acenocoumarol dose, stroke recurrence and intracranial haemorrhage in Spain Cullell, Natalia; Carrera, Caty; Muiño, Elena; Torres-Aguila, Nuria-Paz; Cárcel-Márquez, Jara; González-Sánchez, Jonathan; Gallego Fabrega, Cristina; Molina, Jessica; Besora, Sarah; Sotoca, Javier; Buongiorno, Maria-Teresa; Jiménez-Conde, Jordi; Giralt-Steinhauer, Eva; de Torres-Chacón, Reyes; Montaner, Joan; Mancha, Fernando; Cabezas, Juan A.; Martí Fàbregas, Joan; Prats Sánchez, Luis; Camps Renom, Pol; Purroy Garcia, Francisco; Cambray Carner, Serafí; Freijo, María del Mar; Vives-Bauzá, Cristòfol; Tur, Silvia; Font, Maria-Àngels; López-Cancio, Elena; Hernandez-Perez, Maria; Obach, Victor; Calleja, Ana; Arenillas, Juan; Rodríguez-Yáñez, Manuel; Castillo, José; Sobrino, Tomas; Fernández-Cádenas, Israel; Krupinski, Jerzy (Nature Publishing Group, 2020)Acenocoumarol is an oral anticoagulant with significant interindividual dose variations. Variants in CYP2C9 and VKORC1 have been associated with acenocoumarol maintenance dose. We analysed whether any of the 49 polymorphisms ...