Dystrophic epidermolysis bullosa (DEB) is a rare genodermatosis characterized by extensive fragility of the skin, which forms blisters and scars following a minimal friction or mechanical trauma.[1] It is inherited as either autosomal recessive (RDEB) or dominant (DDEB) manner. DDEB is characterized by a wide range of clinical heterogeneity. Indeed, the blistering tendency can be relatively mild and limited to areas of considerable trauma, as in the DDEB-pretibial (DDEB-pt), or be more generalized, as in the DDEB-generalized (DDEB-gen).[2] A peculiar form of DDEB-gen presents with albopapuloid lesions. DDEB is usually caused by missense mutations in the COL7A1 gene.

Previous studies have underlined the fact that DEB in Tunisia is essentially an autosomal recessive disease because of the high rate of endogamy.[3] However, no data are available on dominant DEB in this country. Here, we report on the first two Tunisian families with DDEB.

Since the mutation screening of COL7A1 is technically laborious and expensive, we performed a PCR for exons 17, 73, 74 and 75 based on the previous DEB Tunisian results.[3] The study was approved by the Institutional Ethics Committee of Institut Pasteur de Tunis.

In family EBD41, a father to daughter transmission of moderate DEB was observed. For family EB-L, the index case EB-L1 presented a RDEB generalized severe (RDEB-GS) and his father a mild and localized DDEB-pt. Clinical features are illustrated on Fig. 1(d–f).


Figure 1. Clinical and molecular features of EB-L and EBD41 families. Pedigrees and molecular results for the two DDEB studied families (EB-L and EBD41). (a) Sequence electropherograms of the sense strand for p.Gly2034Arg in exon 73 (heterozygous profile); (b) the p.Val769Phefs*3 mutation at a heterozygous state in exon 17; (c) heterozygous profile for the c.6161C>T mutation in exon 73; *Positions of the mutations are indicated by arrows; (d) blistering, erosions with mild scarring on the pretibial regions of the EB-LP; (e) widespread blisters, erosions, scars, mitten deformity, significant nail dystrophy and pseudosyndactyly of feet of the EB-L1; (f) albopapuloid lesions, mild lesions on leg and severely dystrophic nails of EBD41-1 patient with DDEB-gen with albopapuloid lesions.

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Genetic screening of family EBD41 showed the presence of a novel dominant substitution, c.6161C>T (p.Ala2054Val), at a heterozygous state in the daughter and the father (EBD41-1, EBD41-P) (Fig. 1c). This variant was not found in 100 control alleles and in silico analysis of the mutated sequence showed that it creates a new donor site (GAGgtagga) within exon 73 (0.75 vs. 0.49 Fruitfly) than the natural (AGGgtgagg) site. The novel donor site (gt) is located 19pb upstream the last nucleotide of exon 73. The usage of this new site would cause the skipping of the last 21-bp of exon 73 leading to the in-frame deletion of seven amino acids (p.Ala2054_Arg2060del) from the collagenous domain of COLVII.

This deleted region is highly conserved among 20 COLVII proteins from different species (Fig. 2). This deletion would occur near the hinge region (HG). It has been shown that mutations close to the HG region interfere with protein folding in a dominant negative manner.[4] Since the clinical features in our two patients (EBD41-1 and EBD41-P) were only moderate, it is possible that the c.6161C>T mutation produces leaky effects,[5] allowing a small amount of normally spliced mRNA to be synthesized and translated into a mutated protein harbouring the p.Ala2054Val missense mutation.


Figure 2. Comparison of AA sequence of human COLVII protein in 20 species at 2054–2060 position. The deleted AA are enclosed within a box. Even if there is a change in an AA, the charge remains the same except in two species (Xenopus tropicalis and Xiphophorus maculatus). In general, the deleted protein fragment is highly conserved through evolution. The deletion, which involves two complete Gly-X-Y collagenous repeats and an alanine residue, would occur near the hinge region (HG).

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In family EB-L, mutation analysis for the prob and EB-L1 revealed the transmission of a maternal deletion/insertion in exon 17 (c.6889delGCinsT) leading to a frame shift and a premature termination of the protein: p.Val769Phefs*3 which is frequent in RDEB Southern Tunisia patients.[3] In addition to the p.Val769Phefs*3 mutation, a frequent dominant glycine-to-arginine substitution (GS) in exon 73 (p.Gly2034Arg) was identified. The severe phenotype observed in EB-L1 could therefore be explained by the rare association of a recessive and a dominant COL7A1 mutation. Previous study showed that the p.Gly2034Arg affects the early stages of anchoring fibrils assembly by altering the formation of procollagen VII antiparallel dimers.[6] The pGly2034Arg is a frequent dominant mutation which was reported with generalized DDEB, DDEB nails only[7] and DDEB pruriginosa.[8] Here, we provide evidence that p.Gly2034Arg could also be responsible for DDEB-pt. Of note, the father (EB-LP) realized that he was affected by a genodermatosis only when his son was diagnosed with RDEB-GS.

In conclusion, prevalence of DDEB is most likely underestimated in Southern Mediterranean countries because of the moderate severity of the disease and low social economic conditions that prevent consulting for relatively mild skin lesions. The identification of carriers of either dominant or recessive mutations is of utmost importance not only to avoid occurrence of the disease among consanguineous families but also to prevent concomitant transmission of both dominant and recessive alleles, which results in more severe phenotypes.


We would like to thank the patients and their families for their collaboration. We also thank Dr Olfa Messaoud for proof reading. This work was supported by the Tunisian Ministry of Higher Education and Scientific Research (Laboratory on ‘Biomedical Genomics and Oncogenetics’ LR11IPT05) and the Tunisian Ministry of Health.


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