title: Compound heterozygosity for non-sense and mis-sense mutations in desmoplakin underlies skin fragility/woolly hair syndrome.
abstract: The constitutive desmosomal plaque protein desmoplakin plays a vital part in keratinocyte adhesion in linking the transmembranous desmosomal cadherins to the cytoplasmic keratin filament network. Recently, mutations in desmoplakin have been shown to underlie some cases of the autosomal dominant disorder, striate palmoplantar keratoderma, as well as an autosomal recessive condition characterized by dilated cardiomyopathy, woolly hair, and keratoderma. Here, we describe two unrelated individuals with a new autosomal recessive genodermatosis characterized by focal and diffuse palmoplantar keratoderma, hyperkeratotic plaques on the trunk and limbs, varying degrees of alopecia, but no apparent cardiac anomalies. Mutation screening of desmoplakin demonstrated compound heterozygosity for a non-sense/mis-sense combination of mutations in both cases, C809X/N287K and Q664X/R2366C, respectively. Heterozygous carriers of any of these mutations displayed no phenotypic abnormalities. Immunohistochemistry of skin biopsies from both affected individuals revealed that desmoplakin was not just located at the cell periphery but there was also cytoplasmic staining. In addition, electron microscopy demonstrated acantholysis throughout all layers of the skin, focal detachment of desmosomes into the intercellular spaces, and perinuclear condensation of the suprabasal keratin intermediate filament network. Clinicopathologic and mutational analyses therefore demonstrate that desmoplakin haploinsufficiency can be tolerated in some cases, but that in combination with a mis-sense mutation on the other allele, the consequences are a severe genodermatosis with specific clinical manifestations.
authors.affiliation: Department of Cellular and Molecular Pathology, St John's Institute of Dermatology, The Guy's, King's College, and St Thomas' Hospitals' Medical School, London, UK. nwhittoc@hgmp.mrc.ac.uk
authors.forename: Neil V
authors.initials: NV
authors.lastname: Whittock
authors.forename: Hong
authors.initials: H
authors.lastname: Wan
authors.forename: Susan M
authors.initials: SM
authors.lastname: Morley
authors.forename: Maria C
authors.initials: MC
authors.lastname: Garzon
authors.forename: Leonard
authors.initials: L
authors.lastname: Kristal
authors.forename: Patrice
authors.initials: P
authors.lastname: Hyde
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Leena
authors.initials: L
authors.lastname: Pulkkinen
authors.forename: Juoni
authors.initials: J
authors.lastname: Uitto
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
authors.forename: Robin A J
authors.initials: RA
authors.lastname: Eady
authors.forename: John A
authors.initials: JA
authors.lastname: McGrath
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D001483:Base Sequence / Q000235:genetics; D018389:Codon, Nonsense / Q000502:physiology*; D000013:Congenital Abnormalities / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D051180:Desmoplakins; D006197:Hair / Q000002:abnormalities*; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007150:Immunohistochemistry; D015603:Keratinocytes / Q000502:physiology / Q000648:ultrastructure; D008854:Microscopy, Electron; D020125:Mutation, Missense / Q000502:physiology*; D010375:Pedigree; D012867:Skin / Q000473:pathology / Q000503:physiopathology; D012871:Skin Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D014018:Tissue Distribution
chemical_list: D018389:Codon, Nonsense; D003598:Cytoskeletal Proteins; C495294:DSP protein, human; D051180:Desmoplakins