title: Single Amino Acid Deletion in Kindlin-1 Results in Partial Protein Degradation Which Can Be Rescued by Chaperone Treatment.
abstract: Kindler syndrome, a distinct type of epidermolysis bullosa, is a rare disorder caused by mutations in FERMT1, encoding kindlin-1. Most FERMT1 mutations lead to premature termination codons and absence of kindlin-1. Here we investigated the molecular and cellular consequences of a naturally occurring FERMT1 mutation, c.299_301del resulting in a single amino acid deletion, p.R100del. The mutation led to a 50% reduction of FERMT1 mRNA and 90% reduction of kindlin-1 protein in keratinocytes derived from the patient, as compared with control cells. The misfolded p.R100del kindlin-1 mutant was lysosomally degraded and launched a homeostatic unfolded protein response. Sodium-phenylbutyrate significantly increased kindlin-1 mRNA and protein levels and the area of mutant cells, acting as a chemical chaperone and probably also as a histone deacetylase inhibitor. In a recombinant system, low levels of wild-type or p.R100del mutant kindlin-1 were sufficient to improve the cellular phenotype in respect of spreading and proliferation as compared with kindlin-1 negative keratinocytes. The study of this hypomorphic mutation provides evidence that low amounts of kindlin-1 are sufficient to improve the epidermal architecture and Kindler syndrome cellular phenotype and proposes a personalized chaperone therapy for the patient.
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany; University of Freiburg, Faculty of Biology, Freiburg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Maier
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Yinghong
authors.initials: Y
authors.lastname: He
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Philipp R
authors.initials: PR
authors.lastname: Esser
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies, University of Freiburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Thriene
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Sarca
authors.affiliation: Private Practice of Human Genetics Freiburg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kohlhase
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany; Freiburg Institute for Advanced Studies, University of Freiburg, Germany.
authors.forename: Jörn
authors.initials: J
authors.lastname: Dengjel
authors.affiliation: Department of Dermatology, Angers University Hospital, Angers, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Martin
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany. Electronic address: cristina.has@uniklinik-freiburg.de.
authors.forename: Cristina
authors.initials: C
authors.lastname: Has
mesh_terms: D000595:Amino Acid Sequence; D001768:Blister / Q000235:genetics* / Q000503:physiopathology; D049109:Cell Proliferation / Q000235:genetics; D002478:Cells, Cultured; D004820:Epidermolysis Bullosa / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease; D006801:Humans; D015151:Immunoblotting; D015603:Keratinocytes / Q000166:cytology* / Q000502:physiology; D008565:Membrane Proteins / Q000235:genetics*; D018832:Molecular Chaperones / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010510:Periodontal Diseases / Q000235:genetics* / Q000503:physiopathology; D010787:Photosensitivity Disorders / Q000235:genetics* / Q000503:physiopathology; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D017384:Sequence Deletion / Q000235:genetics*
chemical_list: C475301:FERMT1 protein, human; D008565:Membrane Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D012333:RNA, Messenger