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 Stoop; Jasper 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

doi:10.1016/j.jid.2023.02.044

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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Abstract

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 language	English
Pages (from-to)	284-295.e16
Number of pages	28
Journal	Journal of Investigative Dermatology
Volume	144
Issue number	2
Early online date	14-Sept-2023
DOIs	https://doi.org/10.1016/j.jid.2023.02.044
Publication status	Published - Feb-2024

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Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar KeratodermaFinal publisher's version, 10.6 MBLicence: CC BY-NC-ND

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Verkerk, A. J. M. H., Andrei, D., Vermeer, M. C. S. C., Kramer, D., Schouten, M., Arp, P., Verlouw, J. A. M., Pas, H. H., Meijer, H. J., van der Molen, M., Oberdorf-Maass, S., Nijenhuis, M., Romero-Herrera, P. H., Hoes, M. F., Bremer, J., Slotman, J. A., van den Akker, P. C., Diercks, G. F. H., Giepmans, B. N. G., ... Bolling, M. C. (2024). Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma. Journal of Investigative Dermatology, 144(2), 284-295.e16. https://doi.org/10.1016/j.jid.2023.02.044

@article{7e38e57f2e214b10976dc80e117898a7,

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

abstract = "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.",

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

year = "2024",

month = feb,

doi = "10.1016/j.jid.2023.02.044",

language = "English",

volume = "144",

pages = "284--295.e16",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "ELSEVIER SCIENCE INC",

number = "2",

}

Verkerk, AJMH, Andrei, D, Vermeer, MCSC , Kramer, D , Schouten, M, Arp, P, Verlouw, JAM, Pas, HH, Meijer, HJ, van der Molen, M, Oberdorf-Maass, S , Nijenhuis, M, Romero-Herrera, PH, Hoes, MF , Bremer, J, Slotman, JA, van den Akker, PC , Diercks, GFH , Giepmans, BNG, Stoop, H, Saris, J, van den Ouweland, AMW, Willemsen, R, Hublin, J-J, Dean, MC, Hoogeboom, AJM, Silljé, HHW, Uitterlinden, AG, van der Meer, P & Bolling, MC 2024, 'Disruption of tuftelin 1, a desmosome associated protein, causes skin fragility, woolly hair and palmoplantar keratoderma', Journal of Investigative Dermatology, vol. 144, no. 2, pp. 284-295.e16. https://doi.org/10.1016/j.jid.2023.02.044

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

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 -

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

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