Reporting COL7A1 gene mutations in five Iranian families with Dystrophic Epidermolysis Bollusa
Maryam Taghdiri1, Sirous Naeimi1*, Majid Fardaei2, Seyed Mohammad Bagher Tabei2,3
1-Department of Genetics, Colleague of science, Kazerun branch, Islamic Azad University, Kazerun, Iran
2-Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran
3- Maternal-fetal Medicine Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
*Corresponding Author: Sirous Naeimi, Department of Genetics, Colleague of science, Kazerun branch, Islamic Azad University, Kazerun, Iran
Email: naeimis@kau.ac.ir
Abstract :
Dystrophic epidermolysis bullosa (DEB) is a rare inherited blistering disorder, characterized by affected dermis-epidermis conjunction.COL7A1 encodes collagen VII protein, which is responsible for dermis-epidermis conjunction. Here we report several mutations ofCOL7A1 in five Iranian families, which result in DEB and expands the mutation spectrum of COL7A1 mutations for further molecular studies.
Key Words: Skin disorder, Dystrophic Epidermolysis Bullosa,COL7A1 , genetic mutations
Key Clinical Message: Different COL7A1 mutations in Iranian families expand the mutations spectrum for further molecular investigation and accurate genetic counseling in affected families.
1. Introduction :
Epidermolysis bullosa (EB) is a rare inherited skin fragility disorder, including fragile skin and mucous membrane as well as body blistering (1). Distinct mutations in the genes encoding cytoskeletal structure of keratinocytes or BMZ can cause EB. EB is classified into 4 main groups depending on clinical and molecular characteristics including EB simplex, dystrophic EB, junctional EB and kindler (2).
Collagen VII is a major component of the anchoring fibrils which plays an important role in dermis and epidermis conjunction. Collagen VII is synthesized as a pro-collagen (pro-α1) in epidermal keratinocytes and dermal fibroblasts. Pro-α 1 (VII) has triple helical central collagenous domain flanked by two non-collagenous globular domains (NC1and NC2). NC1 is responsible for the attachment of anchoring fibrils at amino terminal and NC2 involves in antiparallel dimer formation at carboxyl terminal of collagen VII molecule. Gly-X-Y amino acid repetitions are located in the triple helical segment to assure its accurate conformation. These repeating sequences are disrupted 19 times by non-collagenous regions. These three identical pro-α1 (VII) chains assemble into type VII collagen homotrimers (COLVII) to ensure the dermal-epidermal adhesion. The conservation of COL7A1 protein structure and amino acid sequences show type VII collagen importance as a structural protein (3, 4).
It was initially suggested COL7A1 gene as a candidate gene for dystrophic forms of EB (DEB) due to the structural modification of anchoring fibrils (AFs) or great alterations in its numbers in a result of electron microscopy of the patients. COL7A1 gene (118 exons and 32kb on 3p21) encodes α1 chain of collagen protein VII. With the advancement of next generation sequencing a wide range of mutations were identified in COL7A1 gene. Nature and location of COL7A1mutations are strongly associated with the phenotypes. A large number ofCOL7A1 mutations are located in exon 73 and most of them can lead to premature termination codon (PTC).
Several domains of COL7A1 mediate interactions of macromolecules in the skin and interfere with skin integrity. The affected skin in DEB patients shows the sub-lamina densa cleavage at the level of (AFs) of the dermal-epidermal junction. DEB is a rare inherited blistering disorder with both autosomal recessive (RDEB) and autosomal dominant (DDEB) mode of inheritance.
The severe form of RDEB is primarily caused by premature termination codon (PTC) mutations, which can be attributed to bi-allelic nonsense, frameshift or splice site mutations. In this form, blisters expand through the body especially on the trauma-exposed sites such as fingers which leads to fingers fusion and seems as pseudosyndactyly. In the milder form of RDEB the fingers and nails are exposed to injury and is often resulting from compound heterozygous mutations (a PTC mutation on one allele and a missense mutation on another allele). In this condition, full length COL7A1 polypeptide with altered conformation can be synthesized and affects the stability of AFs structure. DDEB mutations usually involve glycine substitutions within the repeating Gly-X-Y sequences of triple helical domain. However, glycine substitutions were observed in either RDEB or DDEB depending on the position and nature of substitutions (4).
Biopsy of the latest blisters is a necessary process to find the depth of affected tissue and electron microscopy is a gold standard diagnostic procedure but it is not affordable. Immunofluorescence study and genetic mutation analysis are the effective way to identify and classify EB patients (1).
Here in this study, we report COL7A1 disease-causing mutations in five families affected by dystrophic epidermolysis bullosa disorder.