Identification of two rare and novel large deletions in ITGB4 gene causing epidermolysis bullosa with pyloric atresia |
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| Authors: | Ángeles Mencía Marta García Eva García Sara Llames Alexandra Charlesworth Raúl de Lucas Asunción Vicente María José Trujillo‐Tiebas Pablo Coto Marta Costa Ángel Vera Arantxa López‐Pestaña Rodolfo Murillas Guerrino Meneguzzi José Luis Jorcano Claudio J Conti María José Escámez Toledano Marcela del Río Nechaevsky |
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| Affiliation: | 1. Department of Bioengineering, Tissue Engineering and Regenerative Medicine Group (TERMeG), Universidad Carlos III de Madrid, Madrid, Spain;2. Regenerative Medicine Unit, Centro de Investigaciones Energética Medioambientales y Tecnológicas (CIEMAT), Madrid, Spain;3. Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS‐FJD), Madrid, Spain;4. Centro de Investigación Biomédica en Red en Enfermedades Raras (CIBERER), ISCIII, Madrid, Spain;5. Laboratorio de Ingeniería de Tejidos, Centro Comunitario de Sangre y Tejidos de Asturias (CCST) Asturias, Oviedo, Spain;6. French Reference Centre for Inherited Epidermolysis Bullosa, L'Archet Hospital, Nice, Cedex3, France;7. Sección de Dermatología, Hospital Universitario La Paz, Madrid, Spain;8. Servicio de Dermatología, Hospital Sant Joan de Déu, University of Barcelona, Barcelona, Spain;9. Instituto de Investigación Sanitaria de la Fundación Jimenez Diaz (IIS‐FJD), Hospital Universitario Jiménez Díaz, Madrid, Spain;10. Servicio de Dermatología y Neonatología, Hospital Universitario Central de Asturias, Oviedo, Spain;11. Servicio de Dermatología, Complejo Hospitalario Carlos Haya, Málaga, Spain;12. Servicio de Dermatología, Hospital Donostia, Gipuzkoa, Spain;13. INSERM U1081, CNRS UMR7284, University of Nice, Sophia Antipolis, Faculty of Medicine, Nice, France |
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| 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. |
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| Keywords: | epidermolysis bullosa genodermatoses inherited skin diseases ITGB4 mutations pyloric atresia |
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