title: Mutations in CSTA, encoding Cystatin A, underlie exfoliative ichthyosis and reveal a role for this protease inhibitor in cell-cell adhesion.
abstract: Autosomal-recessive exfoliative ichthyosis presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of nonerythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Using whole-genome homozygosity mapping, candidate-gene analysis and deep sequencing, we have identified loss-of-function mutations in the gene for protease inhibitor cystatin A (CSTA) as the underlying genetic cause of exfoliative ichthyosis. We found two homozygous mutations, a splice-site and a nonsense mutation, in two consanguineous families of Bedouin and Turkish origin. Electron microscopy of skin biopsies from affected individuals revealed that the level of detachment occurs in the basal and lower suprabasal layers. In addition, in vitro modeling suggests that in the absence of cystatin A protein, there is a cell-cell adhesion defect in human keratinocytes that is particularly prominent when cells are subject to mechanical stress. We show here evidence of a key role for a protease inhibitor in epidermal adhesion within the lower layers of the human epidermis.
authors.affiliation: Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, UK.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Blaydon
authors.forename: Daniela
authors.initials: D
authors.lastname: Nitoiu
authors.forename: Katja-Martina
authors.initials: KM
authors.lastname: Eckl
authors.forename: Rita M
authors.initials: RM
authors.lastname: Cabral
authors.forename: Philip
authors.initials: P
authors.lastname: Bland
authors.forename: Ingrid
authors.initials: I
authors.lastname: Hausser
authors.forename: David A
authors.initials: DA
authors.lastname: van Heel
authors.forename: Shefali
authors.initials: S
authors.lastname: Rajpopat
authors.forename: Judith
authors.initials: J
authors.lastname: Fischer
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Oji
authors.forename: Alex
authors.initials: A
authors.lastname: Zvulunov
authors.forename: Heiko
authors.initials: H
authors.lastname: Traupe
authors.forename: Hans Christian
authors.initials: HC
authors.lastname: Hennies
authors.forename: David P
authors.initials: DP
authors.lastname: Kelsell
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002448:Cell Adhesion; D055312:Cystatin A / Q000235:genetics*; D004817:Epidermis / Q000378:metabolism; D005192:Family Health; D005260:Female; D005528:Foot / Q000473:pathology; D016678:Genome; D006720:Homozygote; D006801:Humans; D007057:Ichthyosis / Q000235:genetics*; D008297:Male; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011480:Protease Inhibitors / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D013314:Stress, Mechanical
chemical_list: D055312:Cystatin A; D011480:Protease Inhibitors; C026407:CSTA protein, human