Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2014-10-07

AUTHORS

Beatriz Lara, Maria Teresa Martínez, Ignacio Blanco, Cristina Hernández-Moro, Eladio A Velasco, Ilaria Ferrarotti, Francisco Rodriguez-Frias, Laura Perez, Irene Vazquez, Javier Alonso, Manuel Posada, Beatriz Martínez-Delgado

ABSTRACT

BackgroundSevere 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.MethodsA 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.ResultsWe 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.ConclusionFinding 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. More... »

PAGES

125

Journal

TITLE

Respiratory Research

ISSUE

1

VOLUME

15

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12931-014-0125-y

DOI

http://dx.doi.org/10.1186/s12931-014-0125-y

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1016773249

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25287719


Indexing Status Check whether this publication has been indexed by Scopus and Web Of Science using the SN Indexing Status Tool
Incoming Citations Browse incoming citations for this publication using opencitations.net

JSON-LD is the canonical representation for SciGraph data.

TIP: You can open this SciGraph record using an external JSON-LD service: JSON-LD Playground Google SDTT

[
  {
    "@context": "https://springernature.github.io/scigraph/jsonld/sgcontext.json", 
    "about": [
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/11", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Medical and Health Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1102", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Cardiorespiratory Medicine and Haematology", 
        "type": "DefinedTerm"
      }, 
      {
        "id": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/1103", 
        "inDefinedTermSet": "http://purl.org/au-research/vocabulary/anzsrc-for/2008/", 
        "name": "Clinical Sciences", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Adult", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Female", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Heterozygote", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Humans", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Male", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Middle Aged", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Mutation", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "Pedigree", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "RNA Splicing", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "alpha 1-Antitrypsin", 
        "type": "DefinedTerm"
      }, 
      {
        "inDefinedTermSet": "https://www.nlm.nih.gov/mesh/", 
        "name": "alpha 1-Antitrypsin Deficiency", 
        "type": "DefinedTerm"
      }
    ], 
    "author": [
      {
        "affiliation": {
          "alternateName": "Servicio de Neumolog\u00eda, Hospital Universitario Arnau de Vilanova, Lleida, Spain", 
          "id": "http://www.grid.ac/institutes/grid.411443.7", 
          "name": [
            "Servicio de Neumolog\u00eda, Hospital Universitario Arnau de Vilanova, Lleida, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Lara", 
        "givenName": "Beatriz", 
        "id": "sg:person.01320266607.98", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01320266607.98"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Servicio de Neumolog\u00eda, Hospital Universitario Doce de Octubre, Madrid, Spain", 
          "id": "http://www.grid.ac/institutes/grid.144756.5", 
          "name": [
            "Servicio de Neumolog\u00eda, Hospital Universitario Doce de Octubre, Madrid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Mart\u00ednez", 
        "givenName": "Maria Teresa", 
        "id": "sg:person.0667643172.52", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0667643172.52"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Board of Directors of the Alpha-1 Antitrypsin Deficiency Spanish Registry, Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR), Barcelona, Spain", 
          "id": "http://www.grid.ac/institutes/grid.483945.7", 
          "name": [
            "Board of Directors of the Alpha-1 Antitrypsin Deficiency Spanish Registry, Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR), Barcelona, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Blanco", 
        "givenName": "Ignacio", 
        "id": "sg:person.011272620520.78", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011272620520.78"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Grupo de Splicing y C\u00e1ncer, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (CSIC-UVa), Valladolid, Spain", 
          "id": "http://www.grid.ac/institutes/grid.507089.3", 
          "name": [
            "Grupo de Splicing y C\u00e1ncer, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (CSIC-UVa), Valladolid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Hern\u00e1ndez-Moro", 
        "givenName": "Cristina", 
        "id": "sg:person.0674153546.41", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0674153546.41"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Grupo de Splicing y C\u00e1ncer, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (CSIC-UVa), Valladolid, Spain", 
          "id": "http://www.grid.ac/institutes/grid.507089.3", 
          "name": [
            "Grupo de Splicing y C\u00e1ncer, Instituto de Biolog\u00eda y Gen\u00e9tica Molecular (CSIC-UVa), Valladolid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Velasco", 
        "givenName": "Eladio A", 
        "id": "sg:person.01233670304.34", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01233670304.34"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Center for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Department of Molecular Medicine, Section of Pneumology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy", 
          "id": "http://www.grid.ac/institutes/grid.8982.b", 
          "name": [
            "Center for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Department of Molecular Medicine, Section of Pneumology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Ferrarotti", 
        "givenName": "Ilaria", 
        "id": "sg:person.0664755217.18", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0664755217.18"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Servicio de Bioqu\u00edmica, Hospital Universitario Vall d' Hebron, Barcelona, Spain", 
          "id": "http://www.grid.ac/institutes/grid.411083.f", 
          "name": [
            "Servicio de Bioqu\u00edmica, Hospital Universitario Vall d' Hebron, Barcelona, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Rodriguez-Frias", 
        "givenName": "Francisco", 
        "id": "sg:person.0713660460.75", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0713660460.75"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Molecular Genetics Unit, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain", 
          "id": "http://www.grid.ac/institutes/None", 
          "name": [
            "Molecular Genetics Unit, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Perez", 
        "givenName": "Laura", 
        "id": "sg:person.01124630546.01", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01124630546.01"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Molecular Genetics Unit, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain", 
          "id": "http://www.grid.ac/institutes/None", 
          "name": [
            "Molecular Genetics Unit, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Vazquez", 
        "givenName": "Irene", 
        "id": "sg:person.01172743746.53", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01172743746.53"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Human Genetics Area, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain", 
          "id": "http://www.grid.ac/institutes/grid.512887.1", 
          "name": [
            "Human Genetics Area, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Alonso", 
        "givenName": "Javier", 
        "id": "sg:person.012571320022.50", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012571320022.50"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Spain RDR and CIBERER, Madrid, Spain", 
          "id": "http://www.grid.ac/institutes/grid.512887.1", 
          "name": [
            "Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Spain RDR and CIBERER, Madrid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Posada", 
        "givenName": "Manuel", 
        "id": "sg:person.0612210061.88", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0612210061.88"
        ], 
        "type": "Person"
      }, 
      {
        "affiliation": {
          "alternateName": "Molecular Genetics Unit, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain", 
          "id": "http://www.grid.ac/institutes/None", 
          "name": [
            "Molecular Genetics Unit, Instituto de Investigaci\u00f3n en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain"
          ], 
          "type": "Organization"
        }, 
        "familyName": "Mart\u00ednez-Delgado", 
        "givenName": "Beatriz", 
        "id": "sg:person.0724321734.42", 
        "sameAs": [
          "https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0724321734.42"
        ], 
        "type": "Person"
      }
    ], 
    "citation": [
      {
        "id": "sg:pub.10.1038/357605a0", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048738506", 
          "https://doi.org/10.1038/357605a0"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/bf00194233", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1048519402", 
          "https://doi.org/10.1007/bf00194233"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/bf00291385", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1011859640", 
          "https://doi.org/10.1007/bf00291385"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1038/ejhg.2010.246", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1027159976", 
          "https://doi.org/10.1038/ejhg.2010.246"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/bf00287070", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1045440141", 
          "https://doi.org/10.1007/bf00287070"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1186/1750-1172-3-16", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1053473059", 
          "https://doi.org/10.1186/1750-1172-3-16"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1186/bcr3202", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1027444621", 
          "https://doi.org/10.1186/bcr3202"
        ], 
        "type": "CreativeWork"
      }, 
      {
        "id": "sg:pub.10.1007/bf00194647", 
        "sameAs": [
          "https://app.dimensions.ai/details/publication/pub.1051129026", 
          "https://doi.org/10.1007/bf00194647"
        ], 
        "type": "CreativeWork"
      }
    ], 
    "datePublished": "2014-10-07", 
    "datePublishedReg": "2014-10-07", 
    "description": "BackgroundSevere 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.MethodsA 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.ResultsWe 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.ConclusionFinding 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.", 
    "genre": "article", 
    "id": "sg:pub.10.1186/s12931-014-0125-y", 
    "inLanguage": "en", 
    "isAccessibleForFree": true, 
    "isPartOf": [
      {
        "id": "sg:journal.1028525", 
        "issn": [
          "1465-9921", 
          "1465-993X"
        ], 
        "name": "Respiratory Research", 
        "publisher": "Springer Nature", 
        "type": "Periodical"
      }, 
      {
        "issueNumber": "1", 
        "type": "PublicationIssue"
      }, 
      {
        "type": "PublicationVolume", 
        "volumeNumber": "15"
      }
    ], 
    "keywords": [
      "alpha-1 antitrypsin deficiency", 
      "severe AAT deficiency", 
      "AAT deficiency", 
      "SERPINA1 gene", 
      "antitrypsin deficiency", 
      "severe alpha-1 antitrypsin deficiency", 
      "risk of emphysema", 
      "liver disease", 
      "lung emphysema", 
      "serum AAT", 
      "discordant cases", 
      "hereditary condition", 
      "expression of transcripts", 
      "RT-PCR", 
      "independent impact", 
      "pathogenic mutations", 
      "emphysema", 
      "patients", 
      "genetic diagnosis", 
      "composite heterozygote", 
      "deficiency", 
      "disease", 
      "adult siblings", 
      "AAT alleles", 
      "coding mutations", 
      "further support", 
      "exon 1c", 
      "aberrant splicing patterns", 
      "mutations", 
      "alleles", 
      "null alleles", 
      "splicing variants", 
      "variants", 
      "diagnosis", 
      "heterozygote combinations", 
      "regulatory regions", 
      "liver", 
      "genes", 
      "ResultsWe", 
      "risk", 
      "siblings", 
      "subjects", 
      "AAT", 
      "assays", 
      "transcriptional analysis", 
      "transcripts", 
      "heterozygotes", 
      "analysis of transcripts", 
      "expression", 
      "pathogenicity", 
      "donor splice site", 
      "addition", 
      "cases", 
      "analysis", 
      "effect", 
      "splicing patterns", 
      "family", 
      "region", 
      "RNA products", 
      "combination", 
      "patterns", 
      "sites", 
      "support", 
      "end", 
      "exons", 
      "impact", 
      "importance", 
      "complete exons", 
      "splice site", 
      "non-coding regions", 
      "highlights", 
      "duplication", 
      "conditions", 
      "continuum", 
      "splicing process", 
      "vector", 
      "products", 
      "position", 
      "process", 
      "thymine", 
      "introns", 
      "consist"
    ], 
    "name": "Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid", 
    "pagination": "125", 
    "productId": [
      {
        "name": "dimensions_id", 
        "type": "PropertyValue", 
        "value": [
          "pub.1016773249"
        ]
      }, 
      {
        "name": "doi", 
        "type": "PropertyValue", 
        "value": [
          "10.1186/s12931-014-0125-y"
        ]
      }, 
      {
        "name": "pubmed_id", 
        "type": "PropertyValue", 
        "value": [
          "25287719"
        ]
      }
    ], 
    "sameAs": [
      "https://doi.org/10.1186/s12931-014-0125-y", 
      "https://app.dimensions.ai/details/publication/pub.1016773249"
    ], 
    "sdDataset": "articles", 
    "sdDatePublished": "2022-05-10T10:08", 
    "sdLicense": "https://scigraph.springernature.com/explorer/license/", 
    "sdPublisher": {
      "name": "Springer Nature - SN SciGraph project", 
      "type": "Organization"
    }, 
    "sdSource": "s3://com-springernature-scigraph/baseset/20220509/entities/gbq_results/article/article_635.jsonl", 
    "type": "ScholarlyArticle", 
    "url": "https://doi.org/10.1186/s12931-014-0125-y"
  }
]
 

Download the RDF metadata as:  json-ld nt turtle xml License info

HOW TO GET THIS DATA PROGRAMMATICALLY:

JSON-LD is a popular format for linked data which is fully compatible with JSON.

curl -H 'Accept: application/ld+json' 'https://scigraph.springernature.com/pub.10.1186/s12931-014-0125-y'

N-Triples is a line-based linked data format ideal for batch operations.

curl -H 'Accept: application/n-triples' 'https://scigraph.springernature.com/pub.10.1186/s12931-014-0125-y'

Turtle is a human-readable linked data format.

curl -H 'Accept: text/turtle' 'https://scigraph.springernature.com/pub.10.1186/s12931-014-0125-y'

RDF/XML is a standard XML format for linked data.

curl -H 'Accept: application/rdf+xml' 'https://scigraph.springernature.com/pub.10.1186/s12931-014-0125-y'


 

This table displays all metadata directly associated to this object as RDF triples.

324 TRIPLES      22 PREDICATES      128 URIs      111 LITERALS      18 BLANK NODES

Subject Predicate Object
1 sg:pub.10.1186/s12931-014-0125-y schema:about N1125bee3d2ed4639ae41c1d0c410fadf
2 N1469d59290ac4a55911b16ecd162023b
3 N20f35b9f03994dd5af33f60e64fac7fe
4 N76ec8c57e5c2448cb2966d38c135824d
5 N81e66ea47a9c41a89cee48d5f176a9b0
6 Na3ff46fd572844f4b6e009286e8d608d
7 Na665b33370c14183a85ebc23500df9c6
8 Naf6c49d632af4ea2a1b23cadfb6da349
9 Nc7f18a6df34e4091b4fcff936245405f
10 Nd9d2226cf9e142e3bfd400b023f4a42c
11 Nf8f4213b9d2b4ea4ab9ee5548aa8950d
12 anzsrc-for:11
13 anzsrc-for:1102
14 anzsrc-for:1103
15 schema:author N991f4965dec44f5b9840acea15237457
16 schema:citation sg:pub.10.1007/bf00194233
17 sg:pub.10.1007/bf00194647
18 sg:pub.10.1007/bf00287070
19 sg:pub.10.1007/bf00291385
20 sg:pub.10.1038/357605a0
21 sg:pub.10.1038/ejhg.2010.246
22 sg:pub.10.1186/1750-1172-3-16
23 sg:pub.10.1186/bcr3202
24 schema:datePublished 2014-10-07
25 schema:datePublishedReg 2014-10-07
26 schema:description BackgroundSevere 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.MethodsA 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.ResultsWe 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.ConclusionFinding 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.
27 schema:genre article
28 schema:inLanguage en
29 schema:isAccessibleForFree true
30 schema:isPartOf N70fca1479c2745d19130f1b739e960c0
31 Nccb7a9d0111f407db3d3c4d10d4251f7
32 sg:journal.1028525
33 schema:keywords AAT
34 AAT alleles
35 AAT deficiency
36 RNA products
37 RT-PCR
38 ResultsWe
39 SERPINA1 gene
40 aberrant splicing patterns
41 addition
42 adult siblings
43 alleles
44 alpha-1 antitrypsin deficiency
45 analysis
46 analysis of transcripts
47 antitrypsin deficiency
48 assays
49 cases
50 coding mutations
51 combination
52 complete exons
53 composite heterozygote
54 conditions
55 consist
56 continuum
57 deficiency
58 diagnosis
59 discordant cases
60 disease
61 donor splice site
62 duplication
63 effect
64 emphysema
65 end
66 exon 1c
67 exons
68 expression
69 expression of transcripts
70 family
71 further support
72 genes
73 genetic diagnosis
74 hereditary condition
75 heterozygote combinations
76 heterozygotes
77 highlights
78 impact
79 importance
80 independent impact
81 introns
82 liver
83 liver disease
84 lung emphysema
85 mutations
86 non-coding regions
87 null alleles
88 pathogenic mutations
89 pathogenicity
90 patients
91 patterns
92 position
93 process
94 products
95 region
96 regulatory regions
97 risk
98 risk of emphysema
99 serum AAT
100 severe AAT deficiency
101 severe alpha-1 antitrypsin deficiency
102 siblings
103 sites
104 splice site
105 splicing patterns
106 splicing process
107 splicing variants
108 subjects
109 support
110 thymine
111 transcriptional analysis
112 transcripts
113 variants
114 vector
115 schema:name Severe alpha-1 antitrypsin deficiency in composite heterozygotes inheriting a new splicing mutation QOMadrid
116 schema:pagination 125
117 schema:productId N3e85b267d87443f38e59abd8111eccb3
118 N4001a159b9d444188deb7d67ff7617e6
119 N96d1f2f73d024ae79ecf03c53a82d861
120 schema:sameAs https://app.dimensions.ai/details/publication/pub.1016773249
121 https://doi.org/10.1186/s12931-014-0125-y
122 schema:sdDatePublished 2022-05-10T10:08
123 schema:sdLicense https://scigraph.springernature.com/explorer/license/
124 schema:sdPublisher N064fa8fdffdd4b2a9d7287566eb07ef7
125 schema:url https://doi.org/10.1186/s12931-014-0125-y
126 sgo:license sg:explorer/license/
127 sgo:sdDataset articles
128 rdf:type schema:ScholarlyArticle
129 N064fa8fdffdd4b2a9d7287566eb07ef7 schema:name Springer Nature - SN SciGraph project
130 rdf:type schema:Organization
131 N1125bee3d2ed4639ae41c1d0c410fadf schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
132 schema:name Humans
133 rdf:type schema:DefinedTerm
134 N1469d59290ac4a55911b16ecd162023b schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
135 schema:name Middle Aged
136 rdf:type schema:DefinedTerm
137 N20f35b9f03994dd5af33f60e64fac7fe schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
138 schema:name alpha 1-Antitrypsin
139 rdf:type schema:DefinedTerm
140 N3801285113564adbae373f81a7bad1d1 rdf:first sg:person.011272620520.78
141 rdf:rest N5332c645a6cf4dd98a15553b5fda44b9
142 N3e85b267d87443f38e59abd8111eccb3 schema:name doi
143 schema:value 10.1186/s12931-014-0125-y
144 rdf:type schema:PropertyValue
145 N4001a159b9d444188deb7d67ff7617e6 schema:name pubmed_id
146 schema:value 25287719
147 rdf:type schema:PropertyValue
148 N4859f1e47e0e45b19122d406e1d6ee8d rdf:first sg:person.0713660460.75
149 rdf:rest Nba103f2e7d634b92a26705a289bdffbd
150 N4ab02c46fc1a488eafcb440c5e3167ee rdf:first sg:person.0667643172.52
151 rdf:rest N3801285113564adbae373f81a7bad1d1
152 N5332c645a6cf4dd98a15553b5fda44b9 rdf:first sg:person.0674153546.41
153 rdf:rest N7b61ba1cc93845dbbcf22769df57dd8c
154 N56b536cba43942cc989521530002e112 rdf:first sg:person.0664755217.18
155 rdf:rest N4859f1e47e0e45b19122d406e1d6ee8d
156 N70fca1479c2745d19130f1b739e960c0 schema:volumeNumber 15
157 rdf:type schema:PublicationVolume
158 N76ec8c57e5c2448cb2966d38c135824d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
159 schema:name Mutation
160 rdf:type schema:DefinedTerm
161 N7b61ba1cc93845dbbcf22769df57dd8c rdf:first sg:person.01233670304.34
162 rdf:rest N56b536cba43942cc989521530002e112
163 N7c1df72df8494a45833f4d66d73736e6 rdf:first sg:person.012571320022.50
164 rdf:rest N9f48e8ff614c49a7850d7384e34df1b5
165 N81e66ea47a9c41a89cee48d5f176a9b0 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
166 schema:name Adult
167 rdf:type schema:DefinedTerm
168 N96d1f2f73d024ae79ecf03c53a82d861 schema:name dimensions_id
169 schema:value pub.1016773249
170 rdf:type schema:PropertyValue
171 N991f4965dec44f5b9840acea15237457 rdf:first sg:person.01320266607.98
172 rdf:rest N4ab02c46fc1a488eafcb440c5e3167ee
173 N9f48e8ff614c49a7850d7384e34df1b5 rdf:first sg:person.0612210061.88
174 rdf:rest Nd31d0cc036d8490eb015993677f44eca
175 Na3ff46fd572844f4b6e009286e8d608d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
176 schema:name Pedigree
177 rdf:type schema:DefinedTerm
178 Na665b33370c14183a85ebc23500df9c6 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
179 schema:name RNA Splicing
180 rdf:type schema:DefinedTerm
181 Naf6c49d632af4ea2a1b23cadfb6da349 schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
182 schema:name alpha 1-Antitrypsin Deficiency
183 rdf:type schema:DefinedTerm
184 Nba103f2e7d634b92a26705a289bdffbd rdf:first sg:person.01124630546.01
185 rdf:rest Ndda2dc7f4b404cb9a302d43e8deb44f9
186 Nc7f18a6df34e4091b4fcff936245405f schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
187 schema:name Male
188 rdf:type schema:DefinedTerm
189 Nccb7a9d0111f407db3d3c4d10d4251f7 schema:issueNumber 1
190 rdf:type schema:PublicationIssue
191 Nd31d0cc036d8490eb015993677f44eca rdf:first sg:person.0724321734.42
192 rdf:rest rdf:nil
193 Nd9d2226cf9e142e3bfd400b023f4a42c schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
194 schema:name Female
195 rdf:type schema:DefinedTerm
196 Ndda2dc7f4b404cb9a302d43e8deb44f9 rdf:first sg:person.01172743746.53
197 rdf:rest N7c1df72df8494a45833f4d66d73736e6
198 Nf8f4213b9d2b4ea4ab9ee5548aa8950d schema:inDefinedTermSet https://www.nlm.nih.gov/mesh/
199 schema:name Heterozygote
200 rdf:type schema:DefinedTerm
201 anzsrc-for:11 schema:inDefinedTermSet anzsrc-for:
202 schema:name Medical and Health Sciences
203 rdf:type schema:DefinedTerm
204 anzsrc-for:1102 schema:inDefinedTermSet anzsrc-for:
205 schema:name Cardiorespiratory Medicine and Haematology
206 rdf:type schema:DefinedTerm
207 anzsrc-for:1103 schema:inDefinedTermSet anzsrc-for:
208 schema:name Clinical Sciences
209 rdf:type schema:DefinedTerm
210 sg:journal.1028525 schema:issn 1465-9921
211 1465-993X
212 schema:name Respiratory Research
213 schema:publisher Springer Nature
214 rdf:type schema:Periodical
215 sg:person.01124630546.01 schema:affiliation grid-institutes:None
216 schema:familyName Perez
217 schema:givenName Laura
218 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01124630546.01
219 rdf:type schema:Person
220 sg:person.011272620520.78 schema:affiliation grid-institutes:grid.483945.7
221 schema:familyName Blanco
222 schema:givenName Ignacio
223 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.011272620520.78
224 rdf:type schema:Person
225 sg:person.01172743746.53 schema:affiliation grid-institutes:None
226 schema:familyName Vazquez
227 schema:givenName Irene
228 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01172743746.53
229 rdf:type schema:Person
230 sg:person.01233670304.34 schema:affiliation grid-institutes:grid.507089.3
231 schema:familyName Velasco
232 schema:givenName Eladio A
233 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01233670304.34
234 rdf:type schema:Person
235 sg:person.012571320022.50 schema:affiliation grid-institutes:grid.512887.1
236 schema:familyName Alonso
237 schema:givenName Javier
238 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.012571320022.50
239 rdf:type schema:Person
240 sg:person.01320266607.98 schema:affiliation grid-institutes:grid.411443.7
241 schema:familyName Lara
242 schema:givenName Beatriz
243 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.01320266607.98
244 rdf:type schema:Person
245 sg:person.0612210061.88 schema:affiliation grid-institutes:grid.512887.1
246 schema:familyName Posada
247 schema:givenName Manuel
248 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0612210061.88
249 rdf:type schema:Person
250 sg:person.0664755217.18 schema:affiliation grid-institutes:grid.8982.b
251 schema:familyName Ferrarotti
252 schema:givenName Ilaria
253 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0664755217.18
254 rdf:type schema:Person
255 sg:person.0667643172.52 schema:affiliation grid-institutes:grid.144756.5
256 schema:familyName Martínez
257 schema:givenName Maria Teresa
258 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0667643172.52
259 rdf:type schema:Person
260 sg:person.0674153546.41 schema:affiliation grid-institutes:grid.507089.3
261 schema:familyName Hernández-Moro
262 schema:givenName Cristina
263 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0674153546.41
264 rdf:type schema:Person
265 sg:person.0713660460.75 schema:affiliation grid-institutes:grid.411083.f
266 schema:familyName Rodriguez-Frias
267 schema:givenName Francisco
268 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0713660460.75
269 rdf:type schema:Person
270 sg:person.0724321734.42 schema:affiliation grid-institutes:None
271 schema:familyName Martínez-Delgado
272 schema:givenName Beatriz
273 schema:sameAs https://app.dimensions.ai/discover/publication?and_facet_researcher=ur.0724321734.42
274 rdf:type schema:Person
275 sg:pub.10.1007/bf00194233 schema:sameAs https://app.dimensions.ai/details/publication/pub.1048519402
276 https://doi.org/10.1007/bf00194233
277 rdf:type schema:CreativeWork
278 sg:pub.10.1007/bf00194647 schema:sameAs https://app.dimensions.ai/details/publication/pub.1051129026
279 https://doi.org/10.1007/bf00194647
280 rdf:type schema:CreativeWork
281 sg:pub.10.1007/bf00287070 schema:sameAs https://app.dimensions.ai/details/publication/pub.1045440141
282 https://doi.org/10.1007/bf00287070
283 rdf:type schema:CreativeWork
284 sg:pub.10.1007/bf00291385 schema:sameAs https://app.dimensions.ai/details/publication/pub.1011859640
285 https://doi.org/10.1007/bf00291385
286 rdf:type schema:CreativeWork
287 sg:pub.10.1038/357605a0 schema:sameAs https://app.dimensions.ai/details/publication/pub.1048738506
288 https://doi.org/10.1038/357605a0
289 rdf:type schema:CreativeWork
290 sg:pub.10.1038/ejhg.2010.246 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027159976
291 https://doi.org/10.1038/ejhg.2010.246
292 rdf:type schema:CreativeWork
293 sg:pub.10.1186/1750-1172-3-16 schema:sameAs https://app.dimensions.ai/details/publication/pub.1053473059
294 https://doi.org/10.1186/1750-1172-3-16
295 rdf:type schema:CreativeWork
296 sg:pub.10.1186/bcr3202 schema:sameAs https://app.dimensions.ai/details/publication/pub.1027444621
297 https://doi.org/10.1186/bcr3202
298 rdf:type schema:CreativeWork
299 grid-institutes:None schema:alternateName Molecular Genetics Unit, Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain
300 schema:name Molecular Genetics Unit, Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Carretera Majadahonda-Pozuelo Km 2,200, 28220, MajadahondaMadrid, Spain
301 rdf:type schema:Organization
302 grid-institutes:grid.144756.5 schema:alternateName Servicio de Neumología, Hospital Universitario Doce de Octubre, Madrid, Spain
303 schema:name Servicio de Neumología, Hospital Universitario Doce de Octubre, Madrid, Spain
304 rdf:type schema:Organization
305 grid-institutes:grid.411083.f schema:alternateName Servicio de Bioquímica, Hospital Universitario Vall d' Hebron, Barcelona, Spain
306 schema:name Servicio de Bioquímica, Hospital Universitario Vall d' Hebron, Barcelona, Spain
307 rdf:type schema:Organization
308 grid-institutes:grid.411443.7 schema:alternateName Servicio de Neumología, Hospital Universitario Arnau de Vilanova, Lleida, Spain
309 schema:name Servicio de Neumología, Hospital Universitario Arnau de Vilanova, Lleida, Spain
310 rdf:type schema:Organization
311 grid-institutes:grid.483945.7 schema:alternateName Board of Directors of the Alpha-1 Antitrypsin Deficiency Spanish Registry, Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR), Barcelona, Spain
312 schema:name Board of Directors of the Alpha-1 Antitrypsin Deficiency Spanish Registry, Lung Foundation Breathe, Spanish Society of Pneumology (SEPAR), Barcelona, Spain
313 rdf:type schema:Organization
314 grid-institutes:grid.507089.3 schema:alternateName Grupo de Splicing y Cáncer, Instituto de Biología y Genética Molecular (CSIC-UVa), Valladolid, Spain
315 schema:name Grupo de Splicing y Cáncer, Instituto de Biología y Genética Molecular (CSIC-UVa), Valladolid, Spain
316 rdf:type schema:Organization
317 grid-institutes:grid.512887.1 schema:alternateName Human Genetics Area, Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
318 Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Spain RDR and CIBERER, Madrid, Spain
319 schema:name Human Genetics Area, Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Madrid, Spain
320 Instituto de Investigación en Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), Spain RDR and CIBERER, Madrid, Spain
321 rdf:type schema:Organization
322 grid-institutes:grid.8982.b schema:alternateName Center for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Department of Molecular Medicine, Section of Pneumology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
323 schema:name Center for Diagnosis of Inherited Alpha-1 Antitrypsin Deficiency, Department of Molecular Medicine, Section of Pneumology, IRCCS San Matteo Hospital Foundation, University of Pavia, Pavia, Italy
324 rdf:type schema:Organization
 




Preview window. Press ESC to close (or click here)


...