MUTATIONS IN THE PLAKOPHILIN-1 GENE RESULT IN ECTODERMAL DYSPLASIA SKIN FRAGILITY SYNDROME

Members of the armadillo protein gene family, which includes plakoglob in and beta-catenin, have important functions in cytoskeleton/cell mem brane interactions(1,2). These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane(3); in addit ion, they may have pivotal roles in signal transduction pathways and s ignificant effects on cell behaviour during development(4-7). Here, we describe the first human mutations in one of these dual function prot eins, plakophilin 1 (band-6 protein; refs 8-10). The affected individu al has a complete absence of immunostaining for plakophilin 1 in the s kin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the pl akophilin 1 gene (PKP1). Clinically, there are features of both cutane ous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues. Desmosomes in the skin are small and poorly for med with widening of keratinocyte intercellular spaces and perturbed d esmosome/keratin intermediate filament interactions. The molecular fin dings and clinical observations in this patient attest to the dual imp ortance of plakophilin 1 in both cutaneous cell-cell adhesion and epid ermal morphogenesis.