Letter to the Editor
Genetic basis of dominant dystrophic epidermolysis bullosa in tunisian families and co-occurrence of dominant and recessive mutations
Article first published online: 3 AUG 2014
© 2014 European Academy of Dermatology and Venereology
Journal of the European Academy of Dermatology and Venereology
Volume 30, Issue 1, pages 155–157, January 2016
How to Cite
Ben Brick, A.S., Laroussi, N., Mesrati, H., Kefi, R., Ouragini, H., Bchetnia, M., Romdhane, L., Marrakchi, S., Boubaker, M.S., Castiglia, D., Hovnanian, A., Abdelhak, S., Turki, H. and Kharfi, M. (2016), Genetic basis of dominant dystrophic epidermolysis bullosa in tunisian families and co-occurrence of dominant and recessive mutations. Journal of the European Academy of Dermatology and Venereology, 30: 155–157. doi: 10.1111/jdv.12645
- Issue published online: 23 DEC 2015
- Article first published online: 3 AUG 2014
- Tunisian Ministry of Higher Education and Scientific Research. Grant Number: LR11IPT05
- Tunisian Ministry of Health
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. 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). 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. 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. 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).
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. 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, allowing a small amount of normally spliced mRNA to be synthesized and translated into a mutated protein harbouring the p.Ala2054Val missense mutation.
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. 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. The pGly2034Arg is a frequent dominant mutation which was reported with generalized DDEB, DDEB nails only and DDEB pruriginosa. 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.
- 1The classification of inherited epidermolysis bullosa (EB): report of the Third International Consensus Meeting on Diagnosis and Classification of EB. J Am Acad Dermatol 2008; 58: 931–950. Epub 2008/04/01., , et al.
- 2Inherited epidermolysis bullosa: new diagnostic criteria and classification. Clin Dermatol 2012; 30: 70–77., .
- 3Mutational founder effect in recessive dystrophic epidermolysis bullosa families from Southern Tunisia. Arch Dermatol Res 2014; 306(4): 405–11. Epub 2013/10/31., , et al.
- 4The recombinant expression of full-length type VII collagen and characterization of molecular mechanisms underlying dystrophic epidermolysis bullosa. J Biol Chem 2002; 277: 2118–2124. Epub 2001/11/08., , , , .
- 5A novel mutation in the XPA gene associated with unusually mild clinical features in a patient who developed a spindle cell melanoma. Br J Dermatol 2006; 155: 81–88. Epub 2006/06/24., , et al.
- 6Single amino acid substitutions in procollagen VII affect early stages of assembly of anchoring fibrils. J Biol Chem 2005; 280: 191–198. Epub 2004/10/29., , et al.
- 7The international dystrophic epidermolysis bullosa patient registry: an online database of dystrophic epidermolysis bullosa patients and their COL7A1 mutations. Hum Mutat 2011; 32: 1100–1107., , et al.
- 8Study on COL7A1 gene mutation in a epidermolysis bullosa pruriginosa family. Zhonghua Yi Xue Za Zhi 2000; 80: 869–871. Epub 2001/02/24., , .