000			nab a22 7a 4500
999			_c16600 _d16600
003			PC16600
005			20211007140837.0
008			211007b xxu||||| |||| 00| 0 eng d
040			_cH12O
041			_aeng
100			_92657 _aGaratachea, Nuria _eInstituto de Investigación i+12
245	0	0	_aSevere alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid. _h[artículo]
260			_bRespiratory research, _c2014
300			_a15(1):125.
500			_aFormato Vancouver: Lara B, Martínez MT, Blanco I, Hernández Moro C, Velasco EA, Ferrarotti I et al. Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid. Respir Res. 2014 Oct 7;15(1):125.
501			_aPMID: 25287719 PMC4194419
504			_aContiene 46 referencias
520			_aBackground: 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.
710			_9625 _aInstituto de Investigación imas12
856			_uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4194419/ _yAcceso libre
942			_2ddc _cART _n0