title: TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome.
abstract: Acral peeling skin syndrome (APSS) is an autosomal recessive skin disorder characterized by acral blistering and peeling of the outermost layers of the epidermis. It is caused by mutations in the gene for transglutaminase 5, TGM5. Here, we report on clinical and molecular findings in 11 patients and extend the TGM5 mutation database by four, to our knowledge, previously unreported mutations: p.M1T, p.L41P, p.L214CfsX15, and p.S604IfsX9. The recurrent mutation p.G113C was found in 9 patients, but also in 3 of 100 control individuals in a heterozygous state, indicating that APSS might be more widespread than hitherto expected. Using quantitative real-time PCR, immunoblotting, and immunofluorescence analysis, we demonstrate that expression and distribution of several epidermal differentiation markers and corneodesmosin (CDSN) is altered in APSS keratinocytes and skin. Although the expression of transglutaminases 1 and 3 was not changed, we found an upregulation of keratin 1, keratin 10, involucrin, loricrin, and CDSN, probably as compensatory mechanisms for stabilization of the epidermal barrier. Our results give insights into the consequences of TGM5 mutations on terminal epidermal differentiation.
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Pigors
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany.
authors.forename: Dimitra
authors.initials: D
authors.lastname: Kiritsi
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany.
authors.forename: Cristina
authors.initials: C
authors.lastname: Cobzaru
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany.
authors.forename: Agnes
authors.initials: A
authors.lastname: Schwieger-Briel
authors.affiliation: Service of Dermatology, University Hospital Nuestra Señora de Candelaria Carretera del Rosario, Santa Cruz de Tenerife, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Suárez
authors.affiliation: Institute for Maternal and Child Health IRCCS "Burlo Garofolo", Trieste, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Faletra
authors.affiliation: Department of Pathology, Turku University Hospital, Turku, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Aho
authors.affiliation: Department of Dermatology, Turku University Hospital, Turku, Finland.
authors.forename: Leeni
authors.initials: L
authors.lastname: Mäkelä
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany.
authors.forename: Johannes S
authors.initials: JS
authors.lastname: Kern
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany; Freiburg Institute for Advanced Studies, School of Life Sciences-LifeNet, University of Freiburg, Freiburg, Germany.
authors.forename: Leena
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Department of Dermatology, University Freiburg Medical Center, Freiburg, Germany. Electronic address: cristina.has@uniklinik-freiburg.de.
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
mesh_terms: D000328:Adult; D001706:Biopsy; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D003873:Dermatitis, Exfoliative / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D004817:Epidermis / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D007223:Infant; D036341:Intercellular Signaling Peptides and Proteins; D053556:Keratin-1 / Q000378:metabolism; D053550:Keratin-10 / Q000378:metabolism; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010859:Pigmentation Disorders / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D011498:Protein Precursors / Q000378:metabolism; D012871:Skin Diseases / Q000151:congenital; D011503:Transglutaminases / Q000235:genetics*
chemical_list: C109656:CDSN protein, human; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053556:Keratin-1; D011498:Protein Precursors; D053550:Keratin-10; C032253:involucrin; C418703:transglutaminase 5; D011503:Transglutaminases