Recessive Epidermolysis Bullosa Simplex Research Articles

LB1724 Autosomal recessive epidermolysis bullosa simplex caused by missense and inframe mutations in PLEC is associated with minimal or delayed muscular dystrophy and possibly less laboratory abnormalities: A series of nine cases

LB1724 Autosomal recessive epidermolysis bullosa simplex caused by missense and inframe mutations in PLEC is associated with minimal or delayed muscular dystrophy and possibly less laboratory abnormalities: A series of nine cases

A novel KRT14 null mutation leads to autosomal recessive epidermolysis bullosa simplex.

We describe a novel homozygous KRT14 (also known as K14) mutation detected in a patient with a relatively mild form of epidermolysis bullosa simplex (EBS). Our patient harbours loss of function of both alleles of the KRT14 gene. This is the 16th reported mutation of recessive EBS in KRT14.

Damaged Keratin Filament Network Caused by KRT5 Mutations in Localized Recessive Epidermolysis Bullosa Simplex.

Epidermolysis bullosa simplex (EBS) is a blistering dermatosis that is mostly caused by dominant mutations in KRT5 and KRT14. In this study, we investigated one patient with localized recessive EBS caused by novel homozygous c.1474T > C mutations in KRT5. Biochemical experiments showed a mutation-induced alteration in the keratin 5 structure, intraepidermal blisters, and collapsed keratin intermediate filaments, but no quantitative change at the protein levels and interaction between keratin 5 and keratin 14. Moreover, we found that MAPK signaling was inhibited, while desmosomal protein desmoglein 1 (DSG1) was upregulated upon KRT5 mutation. Inhibition of EGFR phosphorylation upregulated DSG1 levels in an in vitro model. Collectively, our findings suggest that this mutation leads to localized recessive EBS and that keratin 5 is involved in maintaining DSG1 via activating MAPK signaling.

Autosomal recessive epidermolysis bullosa simplex due to EXPH5 mutation: neonatal diagnosis of the first Italian case and literature review

Inherited epidermolysis bullosa is a skin fragility disorder typified by blister formation following minor trauma. Four major EB types are distinguished based on the level of cleavage within the skin. Among these, epidermolysis bullosa simplex (EBS) is characterized by blister formation within the basal epidermis. EBS is the most heterogeneous EB type with mutations in seven different genes and a spectrum of clinical manifestations, ranging from widespread life-threatening skin and mucosal involvement to mild localized disease forms.

307 Homozygous Biallelic KRT5 Mutations in Epidermolysis Bullosa Simplex, Including a Complete Human Keratin 5 “Knock-Out”, in Families with Extensive Consanguinity

Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in the KRT5 and KRT14 genes. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in embryonic lethality. We sought the genetic causes of EBS in a cohort of EB patients by performing whole exome sequencing (WES) and using a disease-targeted next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human “knock-out” of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to lethal, expanding the genotypic profile of autosomal recessive EBS.

Biallelic KRT5 mutations in autosomal recessive epidermolysis bullosa simplex, including a complete human keratin 5 “knock-out”

Epidermolysis bullosa simplex (EBS) is usually inherited as an autosomal dominant disease due to monoallelic gain-of-function mutations in KRT5 or KRT14. Although autosomal recessive forms of EBS have been associated with mutations in at least 10 genes, recessive EBS due to homozygous biallelic KRT5 mutations has not been reported previously; it has been hypothesized that it would result in prenatal lethality. We sought the genetic causes of EB in a cohort of 512 distinct EB families by performing whole exome sequencing (WES) and using an EB-targeting next-generation sequencing (NGS) panel of 21 genes. The pathogenicity and consequences of the mutations were determined by expression profiling and at tissue and ultrastructural levels. Two pathogenic, homozygous missense variants of KRT5 in two patients with generalized EBS and a homozygous null mutation in a patient who died as a neonate from complications of EB were found. The two missense mutations disrupted keratin 5 expression on immunofluorescence microscopy, and the human “knock-out” of KRT5 showed no RNA and protein expression. Collectively, these findings identify biallelic KRT5 mutations with a phenotypic spectrum varying from mild, localized and generalized to perinatal lethal, expanding the genotypic profile of autosomal recessive EBS.

807 Revertant mosaicism in the first case of recessive epidermolysis bullosa simplex caused by KRT5 mutations

807 Revertant mosaicism in the first case of recessive epidermolysis bullosa simplex caused by KRT5 mutations

P.179 - PLEC gene mutations cause familial disto-proximal myopathy and long QT syndrome mimicking mitochondrial disease

Plectin, a giant multifunctional cytolinker protein, plays a crucial role in orchestrating intermediate filament networks in a wide variety of tissues, as epithelia, skeletal muscle and heart. Mutations of the plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), EBS-MD with myasthenic features, EBS with pyloric atresia, EBS-Ogna, and LGMD2Q. Here we report an Italian family with a distinctive muscle phenotype and autosomal recessive transmission in which Whole Exome Sequencing identified homozygous mutations in PLEC gene. Three brothers (two female and one male), age 52, 51 and 46 years, were affected in their thirties by adult-onset myopathy characterized by progressive disto-proximal symmetrical muscle weakness, more severe in distal muscles and upper limbs, mild facial weakness, ptosis and strabismus. There were no skin abnormalities. Cardiac investigation showed arrhythmia and long QT syndrome requiring in one patient an Implantable Cardioverter Defibrillator. Cardiac MRI demonstrated late-gadolinium enhancement in the basal inferolateral part of left ventricle, with sub-epicardic distribution pattern and intramural involvement. A fourth sister had died of sudden death at age 16 years. Myopathological analyses showed the typical hallmarks of mitochondrial diseases with numerous RRFs, a chronic myopathic process with necrosis and regeneration, desmin accumulation in some fibers and markedly reduced plectin staining. Muscle respiratory chain activities were normal. This report expands the phenotypes of plectin-associated disorders and supports the hypothesis that mitochondrial dysfunction contributes to the progression and severity of muscle damage in plectin myopathy. “Plectinopathies” represent a diagnostic challenge for their chameleon presentation and this study supports the value of next generation technologies to improve our abilities in diagnosing complex neuromuscular disorders. Analysis of PLEC should be included in the workout of mitochondrial disorders and distal myopathies.

One amino acid deletion in collagen XVII-binding domain of plectin with a truncation mutation underlies epidermolysis bullosa simplex

Epidermolysis bullosa simplex (EBS) is a group of congenital skin fragility disorders characterized by intraepidermal skin detachment. PLEC, encoding plectin, is one of the causative genes responsible for EBS. Plectin deficiency is responsible for two autosomal recessive EBS subtypes: EBS with muscular dystrophy (EBS-MD) and EBS with pyloric atresia (EBS-PA). Plectin is a linker protein between hemidesmosomes and intermediate filaments. Plectin harbors a central rod domain which mediates homodimer formation. Plectin transcripts include both full-length and rodless forms. Previous studies indicate that loss of full-length plectin with the maintenance of rodless plectin leads to EBS-MD, whereas both full-length and rodless plectin isoforms are deficient in EBS-PA. However, a few EBS-MD cases have been reported to have in-frame deletions in the N-terminal globular domain of plectin. The Y domain of plectin (Arg618 to Val819) was implicated in binding to collagen XVII (COL17) in yeast two-hybrid assays. However the relevance of plectin-COL17 binding in EBS has not been uncovered. Here, we introduce an EBS patient harboring one amino acid deletion in the N-terminus globular domain (p.Phe755del) and a truncation mutation (p.Leu3065fs) in plectin. Plectin expression in skin specimens and cultured keratinocytes from the patient was diminished at the protein and the mRNA levels. COL17 expression was reduced at the protein level, whereas no pathogenic mutation was detected in the COL17A1 gene. Phe755, a deleted amino acid in one allele of the patient, is located in the Y domain of plectin (Arg618 to Val819). Our study is the first to demonstrate that defects of plectin-COL17 binding might contribute to the EBS phenotype.

Downstream effects of plectin mutations in epidermolysis bullosa simplex with muscular dystrophy

Mutations of the human plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). In the present study we analyzed the downstream effects of PLEC mutations on plectin protein expression and localization, the structure of the extrasarcomeric desmin cytoskeleton, protein aggregate formation and mitochondrial distribution in skeletal muscle tissue from three EBS-MD patients.PLEC gene analysis in a not previously reported 35-year-old EBS-MD patient with additional disease features of cardiomyopathy and malignant arrhythmias revealed novel compound heterozygous (p.(Phe755del) and p.(Lys1040Argfs*139)) mutations resulting in complete abolition of plectin protein expression. In contrast, the other two patients with different homozygous PLEC mutations showed preserved plectin protein expression with one only expressing rodless plectin variants, and the other markedly reduced protein levels. Analysis of skeletal muscle tissue from all three patients revealed severe disruption of the extrasarcomeric intermediate filament cytoskeleton, protein aggregates positive for desmin, syncoilin, and synemin, degenerative myofibrillar changes, and mitochondrial abnormalities comprising respiratory chain dysfunction and an altered organelle distribution and amount.Our study demonstrates that EBS-MD causing PLEC mutations universally result in a desmin protein aggregate myopathy phenotype despite marked differences in individual plectin protein expression patterns. Since plectin is the key cytolinker protein that regulates the structural and functional organization of desmin filaments, the defective anchorage and spacing of assembled desmin filaments is the key pathogenetic event that triggers the formation of desmin protein aggregates as well as secondary mitochondrial pathology.Electronic supplementary materialThe online version of this article (doi:10.1186/s40478-016-0314-7) contains supplementary material, which is available to authorized users.

Inflammation épithéliale liée à des mutations avec pertes de fonctions du récepteur à l’EGF

Plectin has been characterized as a linker protein that is expressed in many cell types and is distinctive in various isoforms in the N-terminus and around the rod domain due to complicated alternative splicing of PLEC, the gene encoding plectin. Plectin deficiency causes autosomal recessive epidermolysis bullosa simplex (EBS) with involvement of the skin and other organs, such as muscle and gastrointestinal tract, depending on the expression pattern of the defective protein. In addition, a point mutation in the rod domain of plectin leads to autosomal dominant EBS, called as EBS-Ogna. Plectin can be targeted by circulating autoantibodies in subepidermal autoimmune blistering diseases. This review summarizes plectin-related skin diseases, from congenital to autoimmune disorders.

Spectraplakins

Spectraplakins

Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa

Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa

Recessive Epidermolysis Bullosa simplex- A case report

Background:Epidermolysis bullosa simplex (EBS) is characterized by intraepidermal blister formation, most commonly appearing in early infancy. Many variants of EBS exist; the four most common variants are inherited in an autosomal dominant fashion. The recessive forms are rare and less reported in our environment. The objective of this report is to describe the case of a young boy with a rare, recessive variant of EBS born to first-cousin parents. Method: The case records of a twelve-year old Nigerian male being managed at the dermatology clinic of Aminu Kano Teaching Hospital (AKTH), Kano was reviewed. Relevant clinical photographs with informed consent and review of literature were carried out. Results: A 12 year old Nigerian male, product of consanguineous marriage presented to the dermatology clinic with recurrent blistering of the skin since early childhood. The areas of the skin commonly affected include the knees, ankles, wrists and elbows with seasonal variations in the severity of lesions. His immediate younger brother is said to have similar skin lesions. Physical examination and histology were in keeping with EBS. Conclusion: Recessive EBS though rare, does occur in our environment and should be suspected in males with blistering skin conditions that are products of consanguineous marriage. Key words: Epidermolysis bullosa simplex, consanguinity, skin blistering

Corrigenda

British Journal of DermatologyVolume 162, Issue 6 p. 1416-1416 Free Access Corrigenda This article corrects the following: A novel homozygous keratin 14 mutation in a patient with autosomal recessive epidermolysis bullosa simplex and squamous cell carcinoma of the tongue J.O. Baek, H.Y. Lee, S.W. Oh, J.S. Lee, S.C. Kim, J.R. Lee, J.Y. Roh, Volume 162Issue 4British Journal of Dermatology pages: 880-882 First Published online: January 21, 2010 First published: 20 May 2010 https://doi.org/10.1111/j.1365-2133.2010.09840.xAboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat In the article by Baek et al,1 the authors wish to include S. C. Kim as a Corresponding Author. Therefore, please note the following changes to the Correspondence details for this article: Correspondence Joo-Young Roh. E-mail: jyroh1@gilhospital.com Soo Chan Kim. E-mail: kimsc@yuhs.ac The authors apologise for this omission. Reference 1 Baek JO, Lee HY, Oh SW et al. A novel homozygous keratin 14 mutation in a patient with autosomal recessive epidermolysis bullosa simplex and squamous cell carcinoma of the tongue. Br J Dermatol 2010; 162: 880– 2. Wiley Online LibraryCASPubMedWeb of Science®Google Scholar Volume162, Issue6June 2010Pages 1416-1416 ReferencesRelatedInformation

A novel homozygous keratin 14 mutation in a patient with autosomal recessive epidermolysis bullosa simplex and squamous cell carcinoma of the tongue

Epidermolysis bullosa simplex (EBS) is a group of inherited skin disorders characterized by lysis of basal keratinocytes leading to the development of intraepidermal blisters from mild trauma. 1 EBS is known to be an autosomal dominant disorder; however, a few recessive cases have been reported. In EBS, the risk of cutaneous malignancy is not higher than in the normal population. 2 We present a patient who showed generalized blistering after minor trauma followed by brownish reticulated hyperpigmentation and squamous cell carcinoma of the tongue. We identified a novel homozygous KRT14 mutation (E392X) inherited in an autosomal recessive fashion.

Clinical heterogeneity in recessive epidermolysis bullosa due to mutations in the keratin 14 gene, KRT14

Epidermolysis bullosa simplex (EBS), the most common subtype of EB, is usually inherited as an autosomal dominant trait caused by mutations in either the keratin 5 (KRT5) or keratin 14 (KRT14) genes. Recessive EBS (R-EBS) is extremely rare. We present the first Australian patient diagnosed with R-EBS, to our knowledge, and a comprehensive review of genotypes and phenotypes of R-EBS reported cases. The female proband, of Turkish descent with consanguineous parentage, was referred to us at the age of 8 years. Clinically, she had a severe phenotype including generalized blisters, mucosal involvement and EB naevi. Immunofluorescence mapping and electron microscopy were consistent with a diagnosis of EBS. Staining for Keratin 14 (K14) was negative. The basal layer, however, reacted with monoclonal antibodies to keratins 6 (K6) and 16 (K16). Mutation screening from genomic DNA showed that the proband was homozygous for the truncation mutation Y204X in exon 3 of KRT14, and both unaffected parents were heterozygous for a single KRT14 Y204X mutation. The phenotype of our patient is reported in more detail and with longer follow-up than those of others published in the literature. The proband's phenotype was severe as an infant but improved with age, suggesting that an alternative keratin is pairing with K5 in her skin to compensate for the loss of K14--a novel biological compensatory mechanism. It is interesting that K6 and K16 were expressed, as these are normally positive in hyperproliferative skin disorders.

Recessive Epidermolysis Bullosa Simplex Phenotype Reproduced in Vitro: Ablation of Keratin 14 Is Partially Compensated by Keratin 17

Recessive epidermolysis bullosa simplex (REBS) is characterized by generalized cutaneous blistering in response to mechanical trauma. This results from fragility of the basal keratinocytes that lack keratin tonofilaments because of homozygote null mutation in the keratin 14 gene. REBS patients display in addition focal dyskeratotic skin lesions with histology of epidermolytic hyperkeratosis (EHK) and tonofilament clumping in the suprabasal layers of the epidermis. In this study we examined whether it is possible to mimic in vitro the bullous and dyskeratotic cellular phenotype. For this purpose, fibroblasts from nondyskeratotic (K14-/-) and dyskeratotic (K14-/-) skin of a REBS patient and fibroblasts from a healthy donor (K14+/+) were isolated and incorporated into collagen matrices. Subsequently, fresh biopsies originating from the nondyskeratotic and dyskeratotic skin of the patient and from a healthy donor were placed onto the collagen matrices and cultured at the air-liquid interface. Epidermal morphogenesis was evaluated on the basis of tissue morphology and the expression of a series of keratins. The results of the present study indicate that basal cell vacuolization in REBS can be mimicked in vitro but not the EHK. Fibroblasts seem to play an important regulatory role in establishing the REBS phenotype. These findings suggest that wild-type fibroblasts may enhance the stability of K14-/- keratinocytes in vitro.

Disorganization of the desmin cytoskeleton and mitochondrial dysfunction in plectin-related epidermolysis bullosa simplex with muscular dystrophy.

Mutations of the human plectin gene (Plec1) cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD). Here, we report on molecular mechanisms leading to severe dystrophic muscle alterations in EBS-MD. Analysis of a 25-yr-old EBS-MD patient carrying a novel homozygous 16-bp insertion mutation (13803ins16/13803ins16) close to the intermediate filament (IF) binding site of plectin showed severe disorganization of the myogenic IF cytoskeleton. Intermyofibrillar and subsarcolemmal accumulations of assembled but highly unordered desmin filaments may be attributed to impaired desmin binding capability of the mutant plectin. This IF pathology was also associated with severe mitochondrial dysfunction, suggesting that the muscle pathology of EBS-MD caused by IF disorganization leads not only to defects in mechanical force transduction but also to metabolic dysfunction. Beyond EBS-MD, our data may contribute to the understanding of other myopathies characterized by sarcoplasmic IF accumulations such as desminopathies or alpha-B-crystallinopathies.

Partial Revertant Mosaicism of Keratin 14 in a Patient with Recessive Epidermolysis Bullosa Simplex

A patient with recessive epidermolysis bullosa simplex due to a previously described homozygous KRT14 1842-2A-->C splice-site mutation was re-examined, because we unexpectedly found signs of revertant mosaicism. The germline mutation resulted in different aberrant transcripts containing premature termination codons, all leading to truncated keratin 14 proteins. Basal keratinocytes in skin and in culture completely lacked keratin 14 and intermediate filaments. From this keratin 14-/- patient we started cultures from a new skin biopsy and here, we serendipitously found keratinocytes that spontaneously expressed keratin 14. This biopsy had been taken from an area of skin that was clinically affected, because blisters could simply be evoked by gentle rubbing. Immunofluorescence and electron microscopy of additional biopsies from this skin area revealed a mosaic expression of keratin 14 and reappearance of intermediate filaments in basal keratinocytes. Immunoblotting showed a revertant keratin 14 polypeptide with seemingly normal molecular weight. DNA analysis of exon 2 and its flanking intron borders showed no additional mutations in the genomic KRT14 sequence. Analysis of mRNA isolated from mosaic skin keratinocytes revealed an additional in-frame transcript (1844T-->G, 1845Delta6) that codes for an abnormal keratin 14 polypeptide with a two residue deletion and one amino acid change. The re-expression of a revertant, albeit abnormal, keratin 14 polypeptide, so-called partial revertant mosaicism, accounts for the antibody staining pattern and for the reappearance of intermediate filaments, which however, are semifunctional and not able to revert the clinical phenotype. The combination of a keratin 14-positive and a keratin 14-negative cell population in epidermis as well as in cultured keratinocytes suggests that the cellular reversion might be caused by an endogenous factor. We hypothesize that a second somatic modulating factor in the genome that affects the processing of the mutant KRT14 pre-mRNA may underlie this phenomenon.