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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
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Palmoplantar keratoderma caused by a missense variant in CTSB encoding cathepsin B
J Mohamad1,2, L Samuelov1,2, L Malki1,2
1Division of Dermatology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
Clinical and Experimental Dermatology
|July 20, 2020
Summary
A genetic mutation in the CTSB gene causes a rare form of palmoplantar keratoderma (PPK). This gain-of-function mutation increases cathepsin B activity, leading to a dominant inherited skin disorder.
Area of Science:
- Dermatology and Genetics
- Molecular Biology and Biochemistry
Background:
- Palmoplantar keratoderma (PPK) encompasses diverse genetic disorders with varied presentations.
- Accurate genetic analysis is crucial for diagnosing PPK due to its heterogeneity.
Observation:
- A patient presented with severe, diffuse erythematous PPK transgrediens and skin peeling.
- Family history indicated an autosomal dominant inheritance pattern.
Findings:
- Whole exome sequencing identified a heterozygous missense mutation in the CTSB gene (encoding cathepsin B).
- This mutation, predicted to be pathogenic, resulted in increased cathepsin B proteolytic activity, indicating a gain-of-function.
- Previous research linked CTSB gene duplications to erythrokeratolysis hiemalis, another dominant disorder of cornification.
Implications:
- This study identifies the first gain-of-function mutation in CTSB associated with a dominant form of diffuse PPK.
- Understanding this genetic defect advances the diagnosis and potential therapeutic strategies for PPK subtypes.
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