title: Frameshift mutation in the V2 domain of human keratin 1 results in striate palmoplantar keratoderma.
abstract: The striate form of palmoplantar keratoderma is a rare autosomal dominant disorder affecting palm and sole skin. Genetic heterogeneity of striate palmoplantar keratoderma has been demonstrated with pathogenic mutations in the desmosomal proteins desmoplakin and desmoglein 1. We have studied a four-generation family of British descent with striate palmoplantar keratoderma. Ultrastructural studies show that intermediate filaments of suprabasal keratinocytes are finer than those of the basal layer. In addition, desmosome numbers are normal, but their inner plaques and midline structures are attenuated. Microsatellite markers were used to screen candidate loci including the epidermal differentiation complex on 1q, the desmoplakin locus on 6p, the type I and II keratin gene clusters on chromosomes 12q and 17q, and the desmosomal cadherin gene cluster on chromosome 18q. Significant genetic linkage to chromosome 12q was observed using marker D12S368, with a maximum two-point lod score of 3.496 at a recombination fraction of 0. Direct sequencing of the keratin 1 gene revealed a frameshift mutation in exon 9 that leads to the partial loss of the glycine loop motif in the V2 domain and the gain of a novel 70 amino acid peptide. Using expression studies we show that the V2 domain is essential for normal function of keratin intermediate filaments.
authors: Epithelial Genetics Group, Human Genetics Unit, University of Dundee, Ninewells Hospital and Medical School, Dundee, UK. nwhittoc@hgmp.mrc.ac.uk
authors: Neil V
authors: NV
authors: Whittock
authors: Frances J
authors: FJ
authors: Smith
authors: Hong
authors: H
authors: Wan
authors: Rajeev
authors: R
authors: Mallipeddi
authors: W Andrew
authors: WA
authors: Griffiths
authors: Patricia
authors: P
authors: Dopping-Hepenstal
authors: Gabrielle H
authors: GH
authors: Ashton
authors: Robin A
authors: RA
authors: Eady
authors: W H Irwin
authors: WH
authors: McLean
authors: John A
authors: JA
authors: McGrath
mesh_terms: D001483:Base Sequence; D002881:Chromosomes, Human, Pair 12; D004252:DNA Mutational Analysis; D003896:Desmosomes / Q000473:pathology; D004817:Epidermis / Q000473:pathology / Q000648:ultrastructure; D005192:Family Health; D005260:Female; D016368:Frameshift Mutation; D015870:Gene Expression; D008040:Genetic Linkage; D049452:Green Fluorescent Proteins; D006801:Humans; D007202:Indicators and Reagents / Q000378:metabolism; D007633:Keratins / Q000737:chemistry / Q000235:genetics*; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000473:pathology; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D010641:Phenotype; D017434:Protein Structure, Tertiary
chemical_list: D007202:Indicators and Reagents; D008164:Luminescent Proteins; D049452:Green Fluorescent Proteins; D007633:Keratins