Key result
A homozygous splice-site variant in the TUFT1 gene causes loss of TUFT1 protein, leading to skin fragility, woolly hair, and palmoplantar keratoderma in two siblings and a knockout mouse model.
Case Report (n=2)
This study identifies TUFT1 as a desmosome-associated protein essential for epidermal integrity, whose absence causes skin and hair abnormalities without cardiac involvement.
TUFT1 variants may underlie isolated skin fragility; hypothesis-generating for desmosomal disorders and requires validation before clinical adoption.
Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients’ skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients’ phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma. Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients’ skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients’ phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.
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Verkerk et al. (2023) conducted a case report in Skin fragility, woolly hair, and palmoplantar keratoderma (n=2). Homozygous splice-site variant in the TUFT1 gene was evaluated on Phenotypic and cellular changes (acantholysis, perinuclear retraction of intermediate filaments, reduced mechanical stress resistance). A homozygous splice-site variant in the TUFT1 gene causes loss of TUFT1 protein, leading to skin fragility, woolly hair, and palmoplantar keratoderma in two siblings and a knockout mouse model.
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