Content » Vol 100, September

Investigative Report

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

Syed Ashraf Uddin, Nicole Cesarato, Aytaj Humbatova, Axel Schmidt, Fazal ur Rehman, Muhammad Naeem, Abdul Samad Tareen, Sabrina Wolf, Muhammad Anwar Panezai, Holger Thiele, Abdul Wali, Regina Fölster-Holst, Sulman Basit, Muhammad Ayub, Regina C. Betz
DOI: 10.2340/00015555-3634


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 frame­shift event predicted to result in a truncated protein (p.Q2417Sfs*57). The present report de­scribes an apparent COL7A1 missense substitution with an unexpected consequence on splicing that leads to a severe recessive dystrophic epidermolysis bullosa phenotype.


This study examined the genetic cause of a severe form of the blister-forming disease epidermolysis bullosa in 2 affected siblings from Pakistan. Exchange of a single base on gene copies from both parents was found in the COL7A1 gene, which should affect the protein properties. However, computer programs predicted a so-called splice effect (altered removal of the introns of a gene). This was proved experimentally in cell culture. Thus, the study shows that a new splice site was created in exon 94, which resulted in a truncated protein.

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