Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]

Desmosomes are highly organized intercellular adhesive junctions that areparticularly prominent in epidermis and other tissues experiencingmechanical stress. Desmoplakin, a constitutive component of the desmosomalplaque, is the most abundant protein present in such junctions and plays acritical role in linking the intermediate filament network to the plasmamembrane in these tissues. Here we report the first mutation in the geneencoding desmoplakin. The identified mutation, resulting in a null alleleand haploinsufficiency, was observed in genomic DNA from a kindred with thedominantly inherited skin disorder, striate palmoplantar keratoderma.Affected individuals had a linear pattern of skin thickening on the fingersand palms and circumscribed areas of skin thickening on the soles. Affectedskin demonstrated loosening of intercellular connections, disruption ofdesmosome-keratin intermediate filament interactions and a proportion ofrudimentary desmosomal structures. The disorder mapped to chromosome 6p21with a maximum lod score of 10.67. The mutation was a heterozygous C-->Ttransition in exon 4 of the desmoplakin gene and predicted a prematuretermination codon in the N-terminal region of the peptide. This is thefirst reported mutation of desmo-plakin and also the first inherited skindisorder in which haploinsufficiency of a structural component has beenimplicated. It identifies dosage of desmoplakin as critical in maintainingepidermal integrity.