title: Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia.
abstract: Epidermolysis bullosa with pyloric atresia (EB-PA) is a rare autosomal recessive hereditary disease with a variable prognosis from lethal to very mild. EB-PA is classified into Simplex form (EBS-PA: OMIM #612138) and Junctional form (JEB-PA: OMIM #226730), and it is caused by mutations in ITGA6, ITGB4 and PLEC genes. We report the analysis of six patients with EB-PA, including two dizygotic twins. Skin immunofluorescence epitope mapping was performed followed by PCR and direct sequencing of the ITGB4 gene. Two of the patients presented with non-lethal EB-PA associated with missense ITGB4 gene mutations. For the other four, early postnatal demise was associated with complete lack of β4 integrin due to a variety of ITGB4 novel mutations (2 large deletions, 1 splice-site mutation and 3 missense mutations). One of the deletions spanned 278 bp, being one of the largest reported to date for this gene. Remarkably, we also found for the first time a founder effect for one novel mutation in the ITGB4 gene. We have identified 6 novel mutations in the ITGB4 gene to be added to the mutation database. Our results reveal genotype-phenotype correlations that contribute to the molecular understanding of this heterogeneous disease, a pivotal issue for prognosis and for the development of novel evidence-based therapeutic options for EB management.
authors.affiliation: Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain.|Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.
authors.forename: Ángeles
authors.initials: Á
authors.lastname: Mencía
authors.affiliation: Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain.|Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: García
authors.affiliation: Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Laboratorio de Ingeniería de Tejidos, Centro Comunitario de Sangre y Tejidos de Asturias (CCST) Asturias, Oviedo, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: García
authors.affiliation: Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.|Laboratorio de Ingeniería de Tejidos, Centro Comunitario de Sangre y Tejidos de Asturias (CCST) Asturias, Oviedo, Spain.
authors.forename: Sara
authors.initials: S
authors.lastname: Llames
authors.affiliation: French Reference Centre for Inherited Epidermolysis Bullosa, L'Archet Hospital, BP 3079, 06202, Nice, Cedex3, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Charlesworth
authors.affiliation: Sección de Dermatología, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Raúl
authors.initials: R
authors.lastname: de Lucas
authors.affiliation: Servicio de Dermatología, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain.
authors.forename: Asunción
authors.initials: A
authors.lastname: Vicente
authors.affiliation: Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Hospital Universitario Jiménez Díaz, Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Trujillo-Tiebas
authors.affiliation: Servicio de Dermatología y Neonatología, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Coto
authors.affiliation: Servicio de Dermatología y Neonatología, Hospital Universitario Central de Asturias, Oviedo, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Costa
authors.affiliation: Servicio de Dermatología, Complejo Hospitalario Carlos Haya, Málaga, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Vera
authors.affiliation: Servicio de Dermatología, Hospital Donostia, Gipuzkoa, Spain.
authors.forename: Arantxa
authors.initials: A
authors.lastname: López-Pestaña
authors.affiliation: Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Rodolfo
authors.initials: R
authors.lastname: Murillas
authors.affiliation: INSERM U1081, CNRS UMR7284, University of Nice, Sophia Antipolis, Faculty of Medicine, 28 Avenue Valombrose, F-06107, Nice, France.
authors.forename: Guerrino
authors.initials: G
authors.lastname: Meneguzzi
authors.affiliation: Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain.|Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.
authors.forename: José Luis
authors.initials: JL
authors.lastname: Jorcano
authors.affiliation: Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.
authors.forename: Claudio J
authors.initials: CJ
authors.lastname: Conti
authors.affiliation: Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain.|Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: María José
authors.initials: MJ
authors.lastname: Escámez Toledano
authors.affiliation: Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain.|Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain.|Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS-FJD), Madrid, Spain.|Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain.
authors.forename: Marcela
authors.initials: M
authors.lastname: del Río Nechaevsky
mesh_terms: D001706:Biopsy; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000175:diagnosis / Q000235:genetics*; D018604:Epitope Mapping; D000939:Epitopes / Q000737:chemistry; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D039663:Integrin beta4 / Q000235:genetics*; D015603:Keratinocytes / Q000166:cytology; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics; D008856:Microscopy, Fluorescence; D020125:Mutation, Missense; D016133:Polymerase Chain Reaction; D011379:Prognosis; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D014429:Twins, Dizygotic
chemical_list: D000939:Epitopes; C059834:ITGB4 protein, human; D039663:Integrin beta4
keywords: ITGB4 mutations; epidermolysis bullosa; genodermatoses; inherited skin diseases; pyloric atresia