2026-07-21T21:49:16Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/48272025-06-18T06:44:27Zcom_20.500.12105_2052com_20.500.12105_2051col_20.500.12105_19616
Repisalud
author
Lara, Beatriz
author
Varela Martinez, Maria del Carmen
author
Blanco, Ignacio
author
Hernández-Moro, Cristina
author
Velasco, Eladio A
author
Ferrarotti, Ilaria
author
Rodriguez-Frias, Francisco
author
Perez, Laura
author
Vazquez-Dominguez, Irene
author
Alonso, Javier
author
Posada De la Paz, Manuel
author
Martinez-Delgado, Beatriz
funder
Instituto de Salud Carlos III
funder
Ministerio de Economía y Competitividad (España)
funder
Junta de Castilla y León (España)
2017-09-04T16:30:46Z
2017-09-04T16:30:46Z
2014-10-07
Respir Res. 2014 Oct 7;15(1):125.
10.1186/s12931-014-0125-y
1465-993X
Respiratory Research
25287719
http://hdl.handle.net/20.500.12105/4827
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.
eng
Alpha-1 antitrypsin
Allelic variants
Null alleles
QO alleles, Splicing, Minigenes
Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
research article
URL
https://repisalud.isciii.es/bitstreams/ec77aa90-f3d1-4806-a2e5-7a2a12217913/download
File
MD5
45555e70c94ca2d6f2b1f9ed0040f173
1436291
application/pdf
SevereAlpha1AntitrypsinDeficiency_2014.pdf
URL
https://repisalud.isciii.es/bitstreams/f5287a6e-c71e-4216-a665-7d0621f1b591/download
File
MD5
016c005bcbc122e73a89171140cdce10
57919
text/plain
12931_2014_Article_125.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/b40e7b4d-ef94-4a47-9c89-2b9074c3f6a7/download
File
MD5
016c005bcbc122e73a89171140cdce10
57919
text/plain
12931_2014_Article_125.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/9cae9e16-ef10-4990-b8dc-f5d11570c519/download
File
MD5
016c005bcbc122e73a89171140cdce10
57919
text/plain
SevereAlpha1AntitrypsinDeficiency_2014.pdf.txt
URL
https://repisalud.isciii.es/bitstreams/3fd96760-f877-46a0-8dd2-05d38de83ecb/download
File
MD5
7f5e11a576ec0c850d0ce70d763d60c0
57894
text/plain
SevereAlpha1AntitrypsinDeficiency_2014.pdf.txt