title: Sequencing of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes in familial cases of bicuspid aortic valve.
abstract: BACKGROUND
  The purpose of our study was to investigate the potential contribution of germline mutations in NOTCH1, GATA5 and TGFBR1 and TGFBR2 genes in a cohort of Italian patients with familial Bicuspid Aortic Valve (BAV).
  
  
  METHODS
  All the coding exons including adjacent intronic as well as 5' and 3' untranslated (UTR) sequences of NOTCH1, GATA5, TGFBR1 and TGFBR2 genes were screened by direct gene sequencing in 11 index patients (8 males; age = 42 ± 19 years) with familial BAV defined as two or more affected members.
  
  
  RESULTS
  Two novel mutations, a missense and a nonsense mutation (Exon 5, p.P284L; Exon 26, p.Y1619X), were found in the NOTCH1 gene in two unrelated families. The mutations segregated with the disease in these families, and they were not found on 200 unrelated chromosomes from ethnically matched controls. No pathogenetic mutation was identified in GATA5, TGFBR1 and TGFBR2 genes.
  
  
  CONCLUSIONS
  Two novel NOTCH1 mutations were identified in two Italian families with BAV, highlighting the role of a NOTCH1 signaling pathway in BAV and its aortic complications. These findings are of relevance for genetic counseling and clinical care of families presenting with BAV. Future studies are needed in order to unravel the still largely unknown genetics of BAV.
authors.affiliation: CNR Istituto di Fisiologia Clinica, Via Moruzzi 1, Pisa 56124, Italy.
authors.forename: Ilenia
authors.initials: I
authors.lastname: Foffa
authors.forename: Lamia
authors.initials: L
authors.lastname: Ait Alì
authors.forename: Paola
authors.initials: P
authors.lastname: Panesi
authors.forename: Massimiliano
authors.initials: M
authors.lastname: Mariani
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Festa
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Botto
authors.forename: Cecilia
authors.initials: C
authors.lastname: Vecoli
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Andreassi
mesh_terms: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D000293:Adolescent; D000328:Adult; D000368:Aged; D001021:Aortic Valve / Q000002:abnormalities; D000082882:Bicuspid Aortic Valve Disease; D016022:Case-Control Studies; D002877:Chromosomes, Human / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D005260:Female; D050992:GATA5 Transcription Factor / Q000235:genetics*; D014644:Genetic Variation; D005828:Genetics, Population / Q000379:methods; D018095:Germ-Line Mutation; D006349:Heart Valve Diseases / Q000208:ethnology / Q000235:genetics*; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D051881:Receptor, Notch1 / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D020413:3' Untranslated Regions; D020121:5' Untranslated Regions; D018389:Codon, Nonsense; D050992:GATA5 Transcription Factor; C494755:GATA5 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human