title: Genotype-phenotype correlation in skin fragility-ectodermal dysplasia syndrome resulting from mutations in plakophilin 1.
abstract: We report a 42-year-old Japanese man with an unusual autosomal recessive genodermatosis. The clinical features comprised normal skin at birth, loss of scalp hair at 3-months of age after a febrile illness, progressive nail dystrophy during infancy, palmoplantar keratoderma starting around the age of 18 years and trauma-induced skin fragility and blisters noted from the age of 20 years. Skin biopsy of rubbed non-lesional skin revealed widening of spaces between adjacent keratinocytes from the suprabasal layer upwards. Electron microscopy demonstrated a reduced number of hypoplastic desmosomes. Immunohistochemical labeling showed a reduction in intercellular staining for the desmosome component plakophilin 1. Mutation analysis revealed a homozygous intron 11 donor splice site mutation in the plakophilin 1 gene, 2021+1 G>A (GenBank no. Z34974). RT-PCR, using RNA extracted from the skin biopsy, provided evidence for residual low levels of the full-length wild-type transcript (approximately 8%) as well as multiple other near full-length transcripts, one of which was in frame leading to deletion of 17 amino acids from the 9th arm-repeat unit of the plakophilin 1 tail domain. Thus, the molecular findings help explain the clinical features in the patient, who has a similar but milder phenotype to previously reported patients with skin fragility-ectodermal dysplasia syndrome associated with complete ablation of plakophilin 1 (OMIM 604536). This new 'mitis' phenotype provides further clinicopathological evidence for the role of plakophilin 1 in keratinocyte cell-cell adhesion and ectodermal development.
authors: Department of Cell and Molecular Pathology, St John's Institute of Dermatology, Guy's, King's College and St Thomas' Hospitals' Medical School, St Thomas's Hospital, London, UK.
authors: T
authors: T
authors: Hamada
authors: A P
authors: AP
authors: South
authors: Y
authors: Y
authors: Mitsuhashi
authors: T
authors: T
authors: Kinebuchi
authors: O
authors: O
authors: Bleck
authors: G H S
authors: GH
authors: Ashton
authors: Y
authors: Y
authors: Hozumi
authors: T
authors: T
authors: Suzuki
authors: T
authors: T
authors: Hashimoto
authors: R A J
authors: RA
authors: Eady
authors: J A
authors: JA
authors: McGrath
mesh_terms: D000328:Adult; D001483:Base Sequence / Q000235:genetics; D001706:Biopsy; D004252:DNA Mutational Analysis; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D051191:Plakophilins; D011506:Proteins / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000473:pathology / Q000648:ultrastructure; D012873:Skin Diseases, Genetic / Q000235:genetics* / Q000473:pathology
chemical_list: C495335:PKP1 protein, human; D051191:Plakophilins; D011506:Proteins