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Acta Derm Venereol . 2020 Sep 30

Apparent Missense Variant in COL7A1 Causes a Severe Form of Recessive Dystrophic Epidermolysis Bullosa via Effects on Splicing

Evangelos J Giamarellos-Bourboulis, Maria Tsilika, Simone Moorlag, Nikolaos Antonakos, Antigone Kotsaki, Jorge Domínguez-Andrés, Evdoxia Kyriazopoulou, Theologia Gkavogianni, Maria-Evangelia Adami, Georgia Damoraki, Panagiotis Koufargyris, Athanassios Karageorgos, Amalia Bolanou, Hans Koenen, Reinout van Crevel, Dionyssia-Irene Droggiti, George Renieris, Antonios Papadopoulos, Mihai G Netea, Nima Rafati, Junfeng Chen, Amaury Herpin, Mats E Pettersson, Fan Han, Chungang Feng, Ola Wallerman, Carl-Johan Rubin, Sandrine Péron, Arianna Cocco, Mårten Larsson, Christian Trötschel, Ansgar Poetsch, Kai Korsching, Wolfgang Bönigk, Heinz G Körschen, Florian Berg, Arild Folkvord, U Benjamin Kaupp, Manfred Schartl, Leif Andersson, Maike Effern, Michael Hölzel, Carmen Escuriola-Ettingshausen, Günter Auerswald, Christoph Königs, Karin Kurnik, Ute Scholz, Robert Klamroth, Johannes Oldenburg, Swetlana Ladigan-Badura, Deepak B Vangala, Christoph Engel, Karolin Bucksch, Robert Hueneburg, Claudia Perne, Jacob Nattermann, Verena Steinke-Lange, Nils Rahner, Hans K Schackert, Jürgen Weitz, Matthias Kloor, Judith Kuhlkamp, Huu Phuc Nguyen, Gabriela Moeslein, Christian Strassburg, Monika Morak, Elke Holinski-Feder, Reinhard Buettner, Stefan Aretz, Markus Loeffler, Wolff Schmiegel, Christian Pox, Karsten Schulmann, German Consortium for Familial Intestinal Cancer, Nadjib Schahab, Seyid Mansuroglu, Christian Schaefer, Rolf Fimmers, Georg Nickenig, Vedat Tiyerili, Nathalie Niyonzima, Siril S Bakke, Ida Gregersen, Sverre Holm, Øystein Sandanger, Hilde L Orrem, Bjørnar Sporsheim, Liv Ryan, Xiang Yi Kong, Tuva Børresdatter Dahl, Mona Skjelland, Kirsten Krohg Sørensen, Anne Mari Rokstad, Arne Yndestad, Eicke Latz, Lars Gullestad, Geir Ø Andersen, Jan Kristian Damås, Pål Aukrust, Tom E Mollnes, Bente Halvorsen, Terje Espevik, Nekma Meah, Dmitri Wall, Katherine York, Bevin Bhoyrul, Laita Bokhari, Daniel Asz Sigall, Wilma F Bergfeld, Regina C Betz, Ulrike Blume-Peytavi, Valerie Callender, Vijaya Chitreddy, Andrea Combalia, George Cotsarelis, Brittany Craiglow, Jeff Donovan, Samantha Eisman, Paul Farrant, Jack Green, Ramon Grimalt, Matthew Harries, Maria Hordinsky, Alan D Irvine, Satoshi Itami, Victoria Jolliffe, Brett King, Won-Soo Lee, Amy McMichael, Andrew Messenger, Paradi Mirmirani, Elise Olsen, Seth J Orlow, Bianca Maria Piraccini, Adriana Rakowska, Pascal Reygagne, Janet L Roberts, Lidia Rudnicka, Jerry Shapiro, Pooja Sharma, Antonella Tosti, Annika Vogt, Martin Wade, Leona Yip, Abraham Zlotogorski, Rodney D Sinclair, Syed Ashraf Uddin, Nicole Cesarato, Aytaj Humbatova, Axel Schmidt, Fazal urRehman, Muhammad Naeem, Abdul Samad Tareen, Sabrina Wolf, Muhammad Anwar Panezai, Holger Thiele, Abdul Wali, Regina Fölster-Holst, Sulman Basit, Muhammad Ayub, Regina C Betz

Dystrophic epidermolysis bullosa is an inherited skin disorder characterized by fragile skin that is prone to blistering. We report here a consanguineous Pakistani family with two siblings, in whom a severe recessive dystrophic epidermolysis bullosa was suspected. Using whole-exome sequencing for one sibling, the homozygous base substitution c.7249C>G in COL7A1 was identified, and could be confirmed in the other sibling by Sanger sequencing. In our exome data, this mutation was annotated as a missense substitution (p.Gln2417Glu), but in silico tools indicated a possible effect on splicing. Using the ExonTrap vector it was verified that the mutation leads to activation of a cryptic donor splice site, which leads to loss of 26 nucleotides, and a frame-shift event predicted to result in a truncated protein (p.Q2417Sfs*57). The present report de-scribes an apparent COL7A1 missense substitution with an unexpected consequence on splicing that leads to a severe recessive dystrophic epidermolysis bullosa phenotype.

PMID: 32926178