Autosomal 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.

Long-Term Follow-Up Outcomes of 19 Patients with Osteogenesis Imperfecta Type XI and Bruck Syndrome Type I Caused by FKBP10 Variants.

Osteogenesis imperfecta type XI (OI-XI) and Bruck syndrome type I (BS1) are two rare disorders caused by biallelic variants in the FKBP10, characterized by early-onset bone fractures and progressive skeletal deformities. The patients with OI-XI, also co-segregated with autosomal-recessive epidermolysis bullosa simplex caused by KRT14 variant, have been reported. In this study, the follow-up clinical features of the patients with OI-XI and BS1 phenotypes due to biallelic FKBP10 variants are compared. The aim of this study is to investigate the follow-up findings of OI-XI and BS1 phenotypes in patients with the FKBP10 variants. A total of 19 children, ten males and nine females, from 16 unrelated families were included in the study. FKBP10 variants were investigated by next-generation sequencing (NGS) based panel gene test or Sanger sequencing. Seventeen patients were followed between 1.5 and 16.8years, and the last follow-up age was between 2 and 24.6years (median 10.7years). They received intravenous bisphosphonate infusions once every 3months in follow-up period. We identified four different biallelic FKBP10 variants, two of which are novel (c.890_897dup TGATGGAC, p.Gly300Ter and c.1256 + 1G > A) in 16 families. Five of these patients also had findings of epidermolysis bullosa simplex, and the same biallelic c.612T > A (p.Tyr204Ter) variant in KRT14, as well as FKBP10, were identified. Twelve patients were diagnosed with OI-XI; whereas, seven were diagnosed with BS1. The BS1 phenotype was late-onset and the annual fracture number was lower. After bisphosphonate treatment, bone mineral densitometry Z score at L1-L4 increased (p = 0.005) and the number of annual fractures decreased (p = 0.036) in patients with OI-XI. However, no significant effect of bisphosphonate treatment was found on these values in BS1 patients. Despite the treatment, the rate of scoliosis and long bone deformity had increased in both groups at the last examination; and, only two patients could take a few steps with the aid of a walker, while others were not ambulatory, and they used wheelchairs for mobility. We identified two novel variants in FKBP10. Families originating from the same geographic region and having the same variant suggest founder effects. Although the number of fractures decreased with bisphosphonate treatment, none of our patients were able to walk during the follow-up. This study is valuable in terms of showing the follow-up findings of patients with FKBP10 variants for the first time.

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.

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.

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.

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.

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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.

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.

Hemidesmosomes Show Abnormal Association with the Keratin Filament Network in Junctional Forms of Epidermolysis Bullosa

Junctional epidermolysis bullosa is a group of hereditary bullous disorders resulting from defects in several hemidesmosome-anchoring filament components. Because hemidesmosomes are involved not only in keratinocyte-extracellular matrix adherence, but also in normal anchorage of keratin intermediate filaments to the basal keratinocyte membrane, we questioned whether this intracellular function of hemidesmosomes was also perturbed in junctional epidermolysis bullosa. We used quantitative electron microscopic methods to assess certain morphologic features of hemidesmosome-keratin intermediate filaments interactions in skin from normal subjects (n = 11) and from patients with different forms of junctional epidermolysis bullosa (n = 13). In addition, skin from patients with autosomal recessive epidermolysis bullosa simplex with plectin defects (n = 3) or with autosomal recessive dystrophic epidermolysis bullosa (n = 4) were included as controls. Values were expressed as a percentage of the total number of hemidesmosomes counted. In normal skin 83.3% +/- 3.3 (SEM) hemidesmosomes were associated with keratin intermediate filaments and 90.1% +/- 1.9 had inner plaques. In Herlitz junctional epidermolysis bullosa (laminin 5 abnormalities, n = 4) these values were reduced to 45.3% +/- 11.5 (p < 0.001; analysis of variance) and 50.3% +/- 12.8 (p < 0.001), respectively. In junctional epidermolysis bullosa with pyloric atresia (alpha6beta4 abnormalities, n = 3) the values were also reduced [41.8% +/- 7.0 (p < 0.001) and 44.5% +/- 5.7 (p < 0.001), respectively]. In the non-Herlitz group (laminin 5 mutations, n = 3) the counts were 66.7% +/- 7.1 (p > 0.05) and 70.5% +/- 8.5 (p < 0.05), and in skin from patients with bullous pemphigoid antigen 2 mutations (n = 3) the counts were 54.3% +/- 13.8 (p < 0.01) and 57.1% +/- 13.9 (p < 0.01). In epidermolysis bullosa simplex associated with plectin mutations the values were 31.9% +/- 8.9 (p < 0.001) for keratin intermediate filaments association and 39.9% +/- 7.1 (p < 0.001) for inner plaques. Findings in recessive dystrophic epidermolysis bullosa patients' skin were indistinguishable from normal control skin with inner plaques (90.5% +/- 2.5) and keratin intermediate filaments attachment (86.3% +/- 2.1). These findings suggest that the molecular abnormalities underlying different forms of junctional epidermolysis bullosa appear to affect certain critical intracellular functions of hemidesmosomes, such as the normal connections with keratin intermediate filaments. This may have important implications for the maintenance of basal keratinocyte integrity and resilience in junctional epidermolysis bullosa.

Autosomal Recessive Epidermolysis Bullosa Simplex

• With few exceptions, epidermolysis bullosa (EB) simplex is an autosomal dominant disorder characterized by rather localized and recurrent nonscarring blister formation; mucous membranes and other organs are usually uninvolved. Recently, two patients were described with an autosomal recessive form of EB simplex associated with muscular dystrophy. We now describe four additional patients with autosomal recessive EB simplex, three of whom had associated muscular dystrophy or congenital myasthenia gravis. These patients had generalized cutaneous findings, including milia, atrophicscarring, nail dystrophy, and scalp alopecia, which have been classically attributed to either junctional or dystrophic EB. Each patient had significant oral cavity involvement, and in two, marked growth retardation and anemia were also present. Our findings suggest that autosomal recessive EB simplex may be characterized by rather severe cutaneous and extracutaneous disease activity, and may be associated with at least two distinct neuromuscular diseases. ( Arch Dermatol. 1989;125:931-938)