title: Unusual molecular findings in Kindler syndrome.
abstract: Kindler syndrome (KS) is a rare inherited skin disorder with blistering and poikiloderma as its main clinical features. It is caused by loss-of-function mutations in the C20orf42 (KIND1) gene which encodes kindlin-1, an actin cytoskeleton-focal contact-associated protein which is predominantly expressed in keratinocytes. We investigated the molecular basis of KS in a 16-year-old Indian boy who had additional clinical findings, including scleroatrophic changes of the hands and feet, pseudoainhum and early onset of squamous cell carcinoma on his foot. Immunostaining for kindlin-1 in the patient's skin was completely absent and sequencing of C20orf42 (KIND1) genomic DNA showed a homozygous splice-site mutation at the -6 position, IVS9-6T-->A. Amplification and sequencing of cDNA from the skin revealed aberrant splicing with either deletion of exon 10 or deletion of exons 9, 10 and 11, both of which involve loss of the pleckstrin homology domain of kindlin-1 that is thought to play a role in cytoskeletal attachment and integrin-mediated cell signalling. Pathogenic splice-site mutations at the -6 position are unusual and have rarely been reported for any genetic disorder. Collectively, these findings extend the spectrum of clinical and molecular abnormalities in this rare genodermatosis.
authors.affiliation: Genetic Skin Disease Group, St John's Institute of Dermatology, Division of Genetics and Molecular Medicine, The Guy's, King's College and St Thomas' School of Medicine, St Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK. ken.arita@kcl.ac.uk
authors.forename: K
authors.initials: K
authors.lastname: Arita
authors.forename: V
authors.initials: V
authors.lastname: Wessagowit
authors.forename: A C
authors.initials: AC
authors.lastname: Inamadar
authors.forename: A
authors.initials: A
authors.lastname: Palit
authors.forename: H
authors.initials: H
authors.lastname: Fassihi
authors.forename: J E
authors.initials: JE
authors.lastname: Lai-Cheong
authors.forename: C
authors.initials: C
authors.lastname: Pourreyron
authors.forename: A P
authors.initials: AP
authors.lastname: South
authors.forename: J A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D000293:Adolescent; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D022821:RNA Splice Sites / Q000235:genetics; D012873:Skin Diseases, Genetic / Q000235:genetics / Q000473:pathology*; D013577:Syndrome
chemical_list: C475301:FERMT1 protein, human; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D022821:RNA Splice Sites