title: FERMT1 promoter mutations in patients with Kindler syndrome.
abstract: Mutations in the FERMT1 gene, encoding the focal adhesion protein kindlin-1 underlie the Kindler syndrome (KS), an autosomal recessive skin disorder with a phenotype comprising skin blistering, photosensitivity, progressive poikiloderma with extensive skin atrophy, and propensity to skin cancer. The FERMT1 mutational spectrum comprises gross genomic deletions, splice site, nonsense, and frameshift mutations, which are scattered over the coding region spanning exon 2-15. We now report three KS families with mutations affecting the promoter region of FERMT1. Two of these mutations are large deletions (∼38.0 and 1.9 kb in size) and one is a single nucleotide variant (c.-20A>G) within the 5' untranslated region (UTR). Each mutation resulted in loss of gene expression in patient skin or cultured keratinocytes. Reporter assays showed the functional relevance of the genomic regions deleted in our patients for FERMT1 gene transcription and proved the causal role of the c.-20A>G variant in reducing transcriptional activity.
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Has
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: N
authors.initials: N
authors.lastname: Chmel
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Levati
authors.affiliation: Department of Specialised, Experimental and Diagnostic Medicine, University of Bologna, Bologna, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Neri
authors.affiliation: Department of Experimental and Clinical Pharmacology and Toxicology, University of Freiburg, Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Sonnenwald
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Pigors
authors.affiliation: Divisions of Genetics and Dermatology, Deenanath Mangeshkar Hospital & Center Erandawane, Pune, India.
authors.forename: K
authors.initials: K
authors.lastname: Godbole
authors.affiliation: Divisions of Genetics and Dermatology, Deenanath Mangeshkar Hospital & Center Erandawane, Pune, India.
authors.forename: A
authors.initials: A
authors.lastname: Dudhbhate
authors.affiliation: Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Bruckner-Tuderman
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: G
authors.initials: G
authors.lastname: Zambruno
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Castiglia
mesh_terms: D000293:Adolescent; D015415:Biomarkers; D001768:Blister / Q000175:diagnosis / Q000235:genetics*; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D004820:Epidermolysis Bullosa / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010510:Periodontal Diseases / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D010787:Photosensitivity Disorders / Q000175:diagnosis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D012867:Skin / Q000473:pathology; D055815:Young Adult
chemical_list: D015415:Biomarkers; C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins
keywords: FERMT1; Kindler syndrome; adhesion; blistering; epidermolysis bullosa; integrin; kindlin