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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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 languageEnglish
JournalJournal of Investigative Dermatology
Publication statusPublished - 7 Aug 2019


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