Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas

Chavalit Supsrisunjai; Chao-Kai Hsu; Magdalene Michael; Cebric Duval; John Lee; Hsing-San  Yang; Hsin-Yu Huang; Chaikul Thitiwat; Alexandros Onoufriadis; Roberto Steiner; Robert A S Ariëns; Ofer Sarig; Eli Sprecher; M. Eskin-Schwartz; Curt Samlaska; Michael Andrew Simpson; Eduardo Calonje; Madeline Parsons; John Alexander McGrath

Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas

Chavalit Supsrisunjai, Chao-Kai Hsu, Magdalene Michael, Cebric Duval, John Lee, Hsing-San Yang, Hsin-Yu Huang, Chaikul Thitiwat, Alexandros Onoufriadis, Roberto Steiner, Robert A S Ariëns, Ofer Sarig, Eli Sprecher, M. Eskin-Schwartz, Curt Samlaska, Michael Andrew Simpson, Eduardo Calonje, Madeline Parsons, John Alexander McGrath

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Abstract

Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in F13A1 gene encoding factor XIII subunit A, a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has an
allele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and 41 integrins, more prominently for Lys679Met FXIII-A than wild-type. In addition, both the 41 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine- Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may leads to a conformational change in the FXIII-A protein that enhances 4-integrin binding and provide insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

Original language	English
Journal	Journal of Investigative Dermatology
Publication status	Published - 7 Aug 2019

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Dermatofibroma JID DF paper revised 26 JulyAccepted author manuscript, 3.79 MB

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Supsrisunjai, C., Hsu, C.-K., Michael, M., Duval, C., Lee, J., Yang, H.-S., Huang, H.-Y., Thitiwat, C., Onoufriadis, A., Steiner, R., Ariëns, R. A. S., Sarig, O., Sprecher, E., Eskin-Schwartz, M., Samlaska, C., Simpson, M. A., Calonje, E., Parsons, M., & McGrath, J. A. (2019). Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas. Journal of Investigative Dermatology.

@article{470edc33d3874bd8b1baecc584484bf9,

title = "Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas",

abstract = "Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in F13A1 gene encoding factor XIII subunit A, a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has anallele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and 41 integrins, more prominently for Lys679Met FXIII-A than wild-type. In addition, both the 41 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine- Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may leads to a conformational change in the FXIII-A protein that enhances 4-integrin binding and provide insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.",

author = "Chavalit Supsrisunjai and Chao-Kai Hsu and Magdalene Michael and Cebric Duval and John Lee and Hsing-San Yang and Hsin-Yu Huang and Chaikul Thitiwat and Alexandros Onoufriadis and Roberto Steiner and Ari{\"e}ns, {Robert A S} and Ofer Sarig and Eli Sprecher and M. Eskin-Schwartz and Curt Samlaska and Simpson, {Michael Andrew} and Eduardo Calonje and Madeline Parsons and McGrath, {John Alexander}",

year = "2019",

month = aug,

day = "7",

language = "English",

journal = "Journal of Investigative Dermatology",

issn = "0022-202X",

publisher = "Nature Publishing Group",

}

Supsrisunjai, C, Hsu, C-K, Michael, M, Duval, C, Lee, J, Yang, H-S, Huang, H-Y, Thitiwat, C, Onoufriadis, A , Steiner, R, Ariëns, RAS, Sarig, O, Sprecher, E, Eskin-Schwartz, M, Samlaska, C, Simpson, MA, Calonje, E, Parsons, M & McGrath, JA 2019, 'Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas', Journal of Investigative Dermatology.

TY - JOUR

T1 - Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas

AU - Supsrisunjai, Chavalit

AU - Hsu, Chao-Kai

AU - Michael, Magdalene

AU - Duval, Cebric

AU - Lee, John

AU - Yang, Hsing-San

AU - Huang, Hsin-Yu

AU - Thitiwat, Chaikul

AU - Onoufriadis, Alexandros

AU - Steiner, Roberto

AU - Ariëns, Robert A S

AU - Sarig, Ofer

AU - Sprecher, Eli

AU - Eskin-Schwartz, M.

AU - Samlaska, Curt

AU - Simpson, Michael Andrew

AU - Calonje, Eduardo

AU - Parsons, Madeline

AU - McGrath, John Alexander

PY - 2019/8/7

Y1 - 2019/8/7

N2 - Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in F13A1 gene encoding factor XIII subunit A, a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has anallele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and 41 integrins, more prominently for Lys679Met FXIII-A than wild-type. In addition, both the 41 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine- Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may leads to a conformational change in the FXIII-A protein that enhances 4-integrin binding and provide insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

AB - Dermatofibromas are common benign skin lesions, the etiology of which is poorly understood. We identified two unrelated pedigrees in which there was autosomal dominant transmission of multiple dermatofibromas. Whole exome sequencing revealed a rare shared heterozygous missense variant in F13A1 gene encoding factor XIII subunit A, a transglutaminase involved in hemostasis, wound healing, tumor growth, and apoptosis. The variant (p.Lys679Met) has anallele frequency of 0.0002 and is predicted to be a damaging mutation. Recombinant human Lys679Met FXIII-A demonstrated reduced fibrin crosslinking activity in vitro. Of note, treatment of fibroblasts with media containing Lys679Met FXIII-A led to enhanced adhesion, proliferation and type I collagen synthesis. Immunostaining revealed co-localization between FXIII-A and 41 integrins, more prominently for Lys679Met FXIII-A than wild-type. In addition, both the 41 inhibitors and the mutation of the FXIII-A Isoleucine-Leucine- Aspartate-Threonine (ILDT) motif prevented Lys679Met FXIII-A-dependent proliferation and collagen synthesis of fibroblasts. Our data suggest that the Lys679Met mutation may leads to a conformational change in the FXIII-A protein that enhances 4-integrin binding and provide insight into an unexpected role for FXIII-A in the pathobiology of familial dermatofibroma.

M3 - Article

SN - 0022-202X

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

ER -

Coagulation Factor XIII-A Subunit Missense Mutation in the Pathobiology of Autosomal Dominant Multiple Dermatofibromas

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