Ten years of
            <scp>DNA</scp>
            diagnostics of epidermolysis bullosa in the Czech Republic

Kopečková, Lenka; Bučková, Hana; Kýrová, Jana; Gaillyová, Renata; Němečková, Jitka; Jeřábková, Barbora; Veselý, Karel; Stehlı́ková, Kristýna; Fajkusová, Lenka

doi:10.1111/bjd.14370

Cited by 5 publications

(3 citation statements)

References 9 publications

(6 reference statements)

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“…1 In spite of the advanced knowledge of the molecular basis of EB and extensive genetic testing, a number of cases remain genetically unsolved. [2][3][4][5] The most common EB type, EB simplex (MIM: 131800, 131960, 131760, 131900, 609352, and 601001), is mainly caused by monoallelic mutations in KRT5 (MIM: 148040) and KRT14 (MIM: 148066), which encode keratin 5 and keratin 14, respectively, the major intermediate filaments (IFs) expressed in basal keratinocytes of the epidermis. Most KRT5 and KRT14 mutations have a dominant-negative effect and weaken the mechanical resistance of keratin IFs in basal epidermal keratinocytes, resulting in skin cleavage within this epidermal layer.…”

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confidence: 99%

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

Maier

Leppert

et al. 2016

The American Journal of Human Genetics

106

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The genetic basis of epidermolysis bullosa, a group of genetic disorders characterized by the mechanically induced formation of skin blisters, is largely known, but a number of cases still remain genetically unsolved. Here, we used whole-exome and targeted sequencing to identify monoallelic mutations, c.1A>G and c.2T>C, in the translation initiation codon of the gene encoding kelch-like protein 24 (KLHL24) in 14 individuals with a distinct skin-fragility phenotype and skin cleavage within basal keratinocytes. Remarkably, mutation c.1A>G occurred de novo and was recurrent in families originating from different countries. The striking similarities of the clinical features of the affected individuals point to a unique and very specific pathomechanism. We showed that mutations in the translation initiation codon of KLHL24 lead to the usage of a downstream translation initiation site with the same reading frame and formation of a truncated polypeptide. The pathobiology was examined in keratinocytes and fibroblasts of the affected individuals and via expression of mutant KLHL24, and we found mutant KLHL24 to be associated with abnormalities of intermediate filaments in keratinocytes and fibroblasts. In particular, KLHL24 mutations were associated with irregular and fragmented keratin 14. Recombinant overexpression of normal KLHL24 promoted keratin 14 degradation, whereas mutant KLHL24 showed less activity than the normal molecule. These findings identify KLHL24 mutations as a cause of skin fragility and identify a role for KLHL24 in maintaining the balance between intermediate filament stability and degradation required for skin integrity.

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confidence: 99%

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

Maier

Leppert

et al. 2016

The American Journal of Human Genetics

106

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“…The previously reported COL7A1 mutations in DEB, pretibial, are summarized in Figure . Both recessive and dominant inheritance patterns have been observed in DEB, pretibial; one‐third of the reported cases showed a recessive inheritance pattern while two‐thirds showed a dominant inheritance pattern.…”

Section: Discussionmentioning

confidence: 95%

Splice site mutation in COL7A1 resulting in aberrant in‐frame transcripts identified in a case of recessive dystrophic epidermolysis bullosa, pretibial

Masunaga

Kubo

Ishiko

2018

The Journal of Dermatology

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Dystrophic epidermolysis bullosa (DEB), pretibial, a rare subtype of epidermolysis bullosa (EB), is characterized by recurrent blisters and erosions predominantly on the pretibial region. We report the case of a 60-year-old Japanese woman with persistent blistering eruptions and scar formation on the pretibial region and elbows. Mutational analysis revealed a previously reported c.5797C>T mutation in exon 70 (p.R1933X) and a novel c.6348+1G>A mutation in intron 76 of COL7A1. Reverse transcription polymerase chain reaction revealed that the c.6348+1G>A mutation resulted in the skipping of exon 76 (69 bp) and the retention of intron 76 (75 bp), and both transcripts were in-frame. From these results, we diagnosed the patient as having recessive DEB, pretibial. A review of previously reported mutations in DEB, pretibial, revealed that one-third of DEB, pretibial, cases showed a recessive inheritance pattern, and no case had a combination of premature termination codon (PTC)/PTC mutations. The DEB, pretibial, case described herein is the first reported case of a compound heterozygote with PTC/in-frame mutations. Although no special characteristic features of the mutations were identified, a high diversity of COL7A1 mutations was shown even in DEB, pretibial.

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“…A custom capture array was designed to capture exons and adjacent intron sequences of 187 genes of which 2 genes are associated with ALGS (JAG1 and NOTCH2). The technique was described in more detail in our previous studies [16][17][18]. Identified sequence changes were filtered against an in-house list of common gene variants and the frequencies of candidate disease variants were also determined in the ExAC Browser (http://exac.broadinstitute.org), Exome Variant Server (http://evs.gs.washington.edu/EVS/), and the 1000 GenomesProject (www.1000genomes.org/).…”

Section: Mutation Analysismentioning

confidence: 99%

Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic

et al. 2021

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Background: Alagille syndrome (ALGS) is a highly variable multisystem disorder inherited in an autosomal dominant pattern with incomplete penetration. The disorder is caused by mutations in the JAG1 gene, only rarely in the NOTCH2 gene, which gives rise to malformations in multiple organs. Bile duct paucity is the main characteristic feature of the disease. Methods: Molecular-genetic examination of genes JAG1 and NOTCH2 in four probands of Czech origin who complied with the diagnostic criteria of ALGS was performed using targeted next-generation sequencing of genes JAG1 and NOTCH2. Segregation of variants in a family was assessed by Sanger sequencing of parental DNA. Results: Mutations in the JAG1 gene were confirmed in all four probands. We identified two novel mutations: c.3189dupG and c.1913delG. Only in one case, the identified JAG1 mutation was de novo. None of the parents carrying JAG1 pathogenic mutation was diagnosed with ALGS. Conclusion: Diagnosis of the ALGS is complicated due to the absence of clear genotype-phenotype correlations and the extreme phenotypic variability in the patients even within the same family. This fact is of particular importance in connection to genetic counselling and prenatal genetic testing.

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Ten years of DNA diagnostics of epidermolysis bullosa in the Czech Republic

Cited by 5 publications

References 9 publications

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility

Splice site mutation in COL7A1 resulting in aberrant in‐frame transcripts identified in a case of recessive dystrophic epidermolysis bullosa, pretibial

Two Novel Mutations in the JAG1 Gene in Pediatric Patients with Alagille Syndrome: The First Case Series in Czech Republic

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