Homozygous Mutations in the 5 ' Region of the JUP Gene Result in Cutaneous Disease but Normal Heart Development in Children

Rita M. Cabral, Lu Liu, Carol Hogan, Patricia J. C. Dopping-Hepenstal, Beatriz C. Winik, Raul A. Asial, Richard Dobson, Charles A. Mein, Patricia A. Baselaga, Jemima E. Mellerio, Arti Nanda, Maria del Carmen Boente, David P. Kelsell, John A. McGrath, Andrew P. South

    Research output: Contribution to journalArticlepeer-review

    38 Citations (Scopus)

    Abstract

    Desmosomes are intercellular adhesive junctions and attachment sites for the intermediate filament (IF) cytoskeleton, prominent in tissues subject to high levels of mechanical stress such as the epidermis and heart. The obligate desmosomal constituent, plakoglobin (PG), is involved in coupling transmembrane desmosomal components with IFs. PG also contributes to intercellular adhesion through adherens junctions and has additional signaling roles. To date, two mutations in the gene encoding PG, JUP, have been described, and in both instances, patients harboring pathogenic mutations suffered from arrhythmogenic right ventricular cardiomyopathy with or without skin abnormalities. We describe homozygous nonsense mutation, p.S24X, and homozygous splice site mutation, c.468G>A, in the JUP gene that results in skin fragility, diffuse palmoplantar keratoderma, and woolly hair with no symptoms of cardiomyopathy. We show barely detectable levels of PG immunostaining in skin sections from patients harboring these mutations and show that an alternative AUG codon in p.S24X mRNA translates a 42-amino-acid N-terminal truncation. We conclude that PG is required for correct maintenance of skin integrity, and the absence of heart phenotype in patients suggests that aberrant PG expression does not compromise normal human heart development in children. Our findings provide new insight into the distinct roles that PG has in the epidermis and heart.

    Original languageEnglish
    Pages (from-to)1543-1550
    Number of pages8
    JournalJournal of Investigative Dermatology
    Volume130
    Issue number6
    DOIs
    Publication statusPublished - Jun 2010

    Keywords

    • RIGHT-VENTRICULAR CARDIOMYOPATHY
    • GROWTH-FACTOR RECEPTOR
    • BETA-CATENIN
    • HUMAN PLAKOGLOBIN
    • EMBRYONIC HEART
    • NAXOS-DISEASE
    • CADHERIN
    • DOMAINS
    • PROTEIN
    • IDENTIFICATION

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