TY - JOUR
T1 - Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar Keratoderma
AU - Verkerk, Annemieke J M H
AU - Andrei, Daniela
AU - Vermeer, Mathilde C S C
AU - Kramer, Duco
AU - Schouten, Marloes
AU - Arp, Pascal
AU - Verlouw, Joost A M
AU - Pas, Hendri H
AU - Meijer, Hillegonda J
AU - van der Molen, Marije
AU - Oberdorf-Maass, Silke
AU - Nijenhuis, Miranda
AU - Romero-Herrera, Pedro H
AU - Hoes, Martijn F
AU - Bremer, Jeroen
AU - Slotman, Johan A
AU - van den Akker, Peter C
AU - Diercks, Gilles F H
AU - Giepmans, Ben N G
AU - Stoop, Hans
AU - Saris, Jasper
AU - van den Ouweland, Ans M W
AU - Willemsen, Rob
AU - Hublin, Jean-Jacques
AU - Dean, M Christopher
AU - Hoogeboom, A Jeannette M
AU - Silljé, Herman H W
AU - Uitterlinden, André G
AU - van der Meer, Peter
AU - Bolling, Maria C
N1 - Publisher Copyright:
© 2023 The Authors
PY - 2024/2
Y1 - 2024/2
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85177161019&partnerID=8YFLogxK
U2 - 10.1016/j.jid.2023.02.044
DO - 10.1016/j.jid.2023.02.044
M3 - Article
C2 - 37716648
SN - 0022-202X
VL - 144
SP - 284-295.e16
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 2
ER -