Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma

Annemieke J M H Verkerk*, Daniela Andrei, Mathilde C S C Vermeer, Duco Kramer, Marloes Schouten, Pascal Arp, Joost A M Verlouw, Hendri H Pas, Hillegonda J Meijer, Marije van der Molen, Silke Oberdorf-Maass, Miranda Nijenhuis, Pedro H Romero-Herrera, Martijn F Hoes, Jeroen Bremer, Johan A Slotman, Peter C van den Akker, Gilles F H Diercks, Ben N G Giepmans, Hans StoopJasper Saris, Ans M W van den Ouweland, Rob Willemsen, Jean-Jacques Hublin, M Christopher Dean, A Jeannette M Hoogeboom, Herman H W Silljé, André G Uitterlinden, Peter van der Meer, Maria C Bolling

*Corresponding author for this work

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Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss of function variants in desmosomal genes lead to a variety of skin and heart related phenotypes. Here, we report tuftelin 1 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 tuftelin 1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that tuftelin 1 is positioned within the desmosome and its location dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1 knock-out mouse model mimicked the patients' phenotypes. Altogether, this study reveals tuftelin 1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair and palmoplantar keratoderma.

Original languageEnglish
JournalJournal of Investigative Dermatology
Publication statusE-pub ahead of print - 14-Sept-2023

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