TY - JOUR
T1 - Disruption of tuftelin 1, 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 - Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.
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 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.
AB - 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.
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 -