Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome

Abstract

Members of the armadillo protein gene family, which includes plakoglobin and β-catenin, have important functions in cytoskeleton/cell membrane interactions^1,2. These proteins may act as linker molecules at adherens junctions and desmosomes at the plasma membrane³; in addition, they may have pivotal roles in signal transduction pathways and significant effects on cell behaviour during development^4–7. Here, we describe the first human mutations in one of these dual function proteins, plakophilin 1 (band-6 protein; refs 8–10). The affected individual has a complete absence of immunostaining for plakophilin 1 in the skin and is a compound heterozygote for autosomal-recessively inherited premature termination codons of translation on both alleles of the plakophilin 1 gene (PKP1). Clinically, there are features of both cutaneous 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 formed with widening of keratinocyte intercellular spaces and perturbed desmosome/keratin intermediate filament interactions. The molecular findings and clinical observations in this patient attest to the dual importance of plakophilin 1 in both cutaneous cell–cell adhesion and epidermal morphogenesis.