ArticleAmerican journal of human genetics2016
Monoallelic Mutations in the Translation Initiation Codon of KLHL24 Cause Skin Fragility.
Article in American journal of human genetics, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 86 citations in OpenAlex.
- Novel compound heterozygous mutations inFrontiers in cardiovascular medicine · 2026Article
- Isolation and Culture of Epidermolysis Bullosa Cells and Organotypic Skin Models.Methods in molecular biology (Clifton, N.J.) · 2025Article
- Integration of long-read sequencing, DNA methylation and gene expression reveals heterogeneity in Y chromosome segment lengths in phenotypic males with 46,XX testicular disorder/difference of sex development.Biology of sex differences · 2024Article
- EBS in Children with De Novo Pathogenic Variants DisturbingInternational journal of molecular sciences · 2024Article
- Syndromic epidermolysis bullosa simplex subtype due to mutations in theFrontiers in medicine · 2024Article
- Calcium/Calmodulin-Dependent Serine Protein Kinase (Animals : an open access journal from MDPI · 2023Article
- Article
- A translation re-initiation variant in KLHL24 also causes epidermolysis bullosa simplex and dilated cardiomyopathy via intermediate filament degradation.The British journal of dermatology · 2022Article
- Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction.International journal of molecular sciences · 2022Review
- Functional investigation of two simultaneous or separately segregating DSP variants within a single family supports the theory of a dose-dependent disease severity.Experimental dermatology · 2022Article
- Epidermolysis Bullosa-A Different Genetic Approach in Correlation with Genetic Heterogeneity.Diagnostics (Basel, Switzerland) · 2022Review
- Defective protein degradation in genetic disorders.Biochimica et biophysica acta. Molecular basis of disease · 2022Review
- Proteasome-mediated degradation of keratins 7, 8, 17 and 18 by mutant KLHL24 in a foetal keratinocyte model: Novel insight in congenital skin defects and fragility of epidermolysis bullosa simplex with cardiomyopathy.Human molecular genetics · 2022Article
- Cardiomyopathies in Children and Systemic Disorders When Is It Useful to Look beyond the Heart?Journal of cardiovascular development and disease · 2022Review
- Keratins as an Inflammation Trigger Point in Epidermolysis Bullosa Simplex.International journal of molecular sciences · 2021Review
- Gain-of-function mutation in ubiquitin-ligase KLHL24 causes desmin degradation and dilatation in hiPSC-derived engineered heart tissues.The Journal of clinical investigation · 2021Article
- Article
- Clinical practice guidelines for laboratory diagnosis of epidermolysis bullosa.The British journal of dermatology · 2020Article
- Genome-Wide Analysis of Methylation-Driven Genes and Identification of an Eight-Gene Panel for Prognosis Prediction in Breast Cancer.Frontiers in genetics · 2020Article
- Epidermolysis bullosa: Advances in research and treatment.Experimental dermatology · 2019Review
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Authors and funding
16 authors at 8 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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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