Browse
Submit Data
Databases
API
Help

Dataset Information

16 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Case Report: De novo KLHL24 Gene Pathogenic Variants in Chinese Twin Boys With Epidermolysis Bullosa Simplex.

ABSTRACT: Objectives: The aim of this study was to determine the molecular etiology and clinical manifestations of a pair of Chinese twins affected with epidermolysis bullosa simplex. Pediatricians should pay attention to the early genetic diagnosis of this disease. Methods: Histopathological examination of HE-stained skin, electron microscopy of biopsied normal skin, and whole-exome sequencing was performed to assess pathogenicity and conservation of detected mutations. Two years later, the cutaneous and extracutaneous manifestations of the twins were comprehensively evaluated. Results: A de novo pathogenic variant c.2T>C (p.M1T) in KLHL24 (NM_017,644) was identified in both twins. The characteristics of extensive skin defects on the extremities at birth and the tendency to lesson with increasing age were confirmed. No positive sensitive markers, such as B-type natriuretic peptide, cardiac troponin I, for cardiac dysfunction were detected. Conclusions: The de novo pathogenic variants c.2T>C (p.M1T) in KLHL24 (NM_017,644) contributes to the development of epidermolysis bullosa. Genetic diagnosis at birth or early infancy can better predict the disease prognosis and guide the treatment.

SUBMITTER: Xu X

PROVIDER: S-EPMC8602111 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

A de novo mutation in KRT5 in a crossbred calf with epidermolysis bullosa simplex.

Project description:A 6-day-old Belgian Blue-Holstein calf was referred because of a syndrome resembling epidermolysis bullosa simplex (EBS). The clinical phenotype included irregular and differently sized erosions and ulcerations spread over the body, in particular on the limbs and over bone prominences, as well as in the nasal planum and oral mucosa. Blisters were easily induced by rubbing the skin. The skin lesions displayed a clear dermal-epidermal separation at the level of the basal cell layer. Post mortem examination revealed erosions in the pharynx, proximal esophagus, and rumen. Whole-genome sequencing revealed a heterozygous disruptive in-frame deletion variant in KRT5 (c.534_536delCAA). Genotyping of both parents confirmed the variant as de novo mutation. Clinicopathological and genetic findings were consistent with the diagnosis of KRT5-related EBS providing the second example of a spontaneous mutation causing epidermolysis bullosa in cattle.

| S-EPMC7694802 | biostudies-literature

A Drosophila Model of Epidermolysis Bullosa Simplex.

Project description:The blistering skin disorder epidermolysis bullosa simplex (EBS) results from dominant mutations in keratin 5 (K5) or keratin 14 (K14) genes, encoding the intermediate filament (IF) network of basal epidermal keratinocytes. The mechanisms governing keratin network formation and collapse due to EBS mutations remain incompletely understood. Drosophila lacks cytoplasmic IFs, providing a 'null' environment to examine the formation of keratin networks and determine mechanisms by which mutant keratins cause pathology. Here, we report that ubiquitous co-expression of transgenes encoding wild-type human K14 and K5 resulted in the formation of extensive keratin networks in Drosophila epithelial and non-epithelial tissues, causing no overt phenotype. Similar to mammalian cells, treatment of transgenic fly tissues with phosphatase inhibitors caused keratin network collapse, validating Drosophila as a genetic model system to investigate keratin dynamics. Co-expression of K5 and a K14(R125C) mutant that causes the most severe form of EBS resulted in widespread formation of EBS-like cytoplasmic keratin aggregates in epithelial and non-epithelial fly tissues. Expression of K14(R125C)/K5 caused semi-lethality; adult survivors developed wing blisters and were flightless due to a lack of intercellular adhesion during wing heart development. This Drosophila model of EBS is valuable for the identification of pathways altered by mutant keratins and for the development of EBS therapies.

| S-EPMC4519992 | biostudies-literature

Microarray analysis of Epidermolysis bullosa simplex-mottled pigmentation

Project description:The goal of this study is to characterize the expression profile of Epidermolysis bullosa simplex-mottled pigmentation (EBS-MP) patient compared with normal subjects using genomic expression analyses. Microarray analyses were performed with RNA isolated from skin biopsies. Robust multiarray analysis (RMA) normalization and Smyth’s moderated t test were used to select differentially expressed genes. Expression profiling comparisons show that 52 genes are differentially expressed in EBS-MP patients compared to control subjects. Difference of expression for three genes (TYR, CCL22 , and ACVR1C ) was validated using real-time reverse transcription–polymerase chain reaction. Twelve genes were related to lipid biosynthesis process, two to keratinisation and skin pigmentation, Nineteen to cell growth and apoptosis, five to immune response and fourteen to predicted or less known function cluster. To our knowledge, the distinctive pattern of gene expression that characterizes EBS-MP versus healthy skin tissue has never been reported. RNA used for the microarrays analysis was isolated from superficial 2mm punch biopsies composed of mainly epidermis with minimal dermis amounts of normal-appearing skin of one EBS-MP patient and seven healthy volunteers.

2012-03-10 | E-GEOD-36406 | biostudies-arrayexpress

Known and novel mutations responsible for epidermolysis bullosa simplex cases in a Chinese population.

Project description:Epidermolysis bullosa simplex, generalized severe (EBS-gen sev) is one of the major forms of EBS, caused by mutations of the keratin 5 (KRT5) or keratin 14 (KRT14). However, it is rarely reported in the Chinese population. The current study was performed on three unrelated Chinese families with five patients clinically suspicious for distinct stages of EBS. Mutation screening was performed by direct sequencing of the entire coding regions of KRT5 and KRT14 genes. A diagnosis of EBS-gen sev for patients in these three families was confirmed by revealing missense mutations c.373C>T (p.Arg125Cys), c.374G>T (p.Arg125Leu), and a novel frameshift mutation c.1231delG (p.Glu411Argfs*31) in KRT14. Considering two previously reported cases and the results of the current report, amino acid residue 125 is likely the most frequent hotspot of EBS-gen sev in the Chinese population. The current study further indicated that the symptoms of EBS-gen sev patients decline with age.

| S-EPMC6862070 | biostudies-literature

Microarray analysis of Epidermolysis bullosa simplex-mottled pigmentation

2012-03-10 | GSE36406 | GEO

Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex.

Project description:Epidermolysis bullosa simplex (EBS) is a group of inherited keratinopathies that, in most cases, arise due to mutations in keratins and lead to intraepidermal ruptures. The cellular pathology of most EBS subtypes is associated with the fragility of the intermediate filament network, cytolysis of the basal layer of the epidermis, or attenuation of hemidesmosomal/desmosomal components. Mutations in keratins 5/14 or in other genes that encode associated proteins induce structural disarrangements of different strengths depending on their locations in the genes. Keratin aggregates display impaired dynamics of assembly and diminished solubility and appear to be the trigger for endoplasmic reticulum (ER) stress upon being phosphorylated by MAPKs. Global changes in cellular signaling mainly occur in cases of severe dominant EBS mutations. The spectrum of changes initiated by phosphorylation includes the inhibition of proteasome degradation, TNF-α signaling activation, deregulated proliferation, abnormal cell migration, and impaired adherence of keratinocytes. ER stress also leads to the release of proinflammatory danger-associated molecular pattern (DAMP) molecules, which enhance avalanche-like inflammation. Many instances of positive feedback in the course of cellular stress and the development of sterile inflammation led to systemic chronic inflammation in EBS. This highlights the role of keratin in the maintenance of epidermal and immune homeostasis.

| S-EPMC8624175 | biostudies-literature

Novel keratin 5 mutation in a family with epidermolysis bullosa simplex.

Project description:The aim of the present study was to identify the causative gene defects associated with epidermolysis bullosa simplex (EBS) in a pedigree. The diagnosis of EBS was confirmed in two patients from that pedigree based on the clinical manifestations, histopathological examination of the skin and family history. Blood samples were collected from 6 family members and 100 heathy controls, and genomic DNA and RNA were extracted. Mutation analysis of the keratin 5 gene (KRT5) was conducted using polymerase chain reaction (PCR) direct sequencing and PCR-restriction fragment length polymorphism. In the pedigree, the results of PCR direct sequencing revealed a heterozygous missense mutation in codon 202 of exon 2 of KRT5 (c.605T>A), which led to an amino acid change (p.L202Q) in the patients with EBS but was absent from the unaffected family members and 100 population controls. In conclusion, a novel missense mutation in the KRT5 gene was identified that had a pathogenic role in EBS in the population studied, which enriches the germline mutation spectrum of the KRT5 gene.

| S-EPMC4665702 | biostudies-literature

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

Project description: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.

| S-EPMC4847350 | biostudies-literature

An inducible mouse model for epidermolysis bullosa simplex: implications for gene therapy.

Project description:The Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) is a severe blistering disease inherited in an autosomal-dominant fashion. Here we report the generation of a mouse model that allows focal activation of a mutant keratin 14 allele in epidermal stem cells upon topical administration of an inducer, resulting in EBS phenotypes in treated areas. Using laser capture microdissection, we show that induced blisters healed by migration of surrounding nonphenotypic stem cells into the wound bed. This observation provides an explanation for the lack of mosaic forms of EBS-DM. In addition, we show that decreased mutant keratin 14 expression resulted in normal morphology and functions of the skin. Our results have important implications for gene therapy of EBS and other dominantly inherited diseases.

| S-EPMC2195993 | biostudies-literature

Epidermolysis bullosa simplex with muscular dystrophy associated with <i>PLEC</i> deletion mutation.

Project description:Epidermolysis bullosa simplex with muscular dystrophy (EBS-MD; OMIM #226670) is an autosomal recessive disorder characterized by neonatal blistering and later-onset muscle weakness.

| S-EPMC5061415 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data