Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantarkeratoderma

Desmosomes are highly organized intercellular adhesive junctions that are p articularly prominent in epidermis and other tissues experiencing mechanica l stress. Desmoplakin, a constitutive component of the desmosomal plaque, i s the most abundant protein present in such junctions and plays a critical role in linking the intermediate filament network to the plasma membrane in these tissues. Here we report the first mutation in the gene encoding desm oplakin. The identified mutation, resulting in a null allele and haploinsuf ficiency, was observed in genomic DNA from a kindred with the dominantly in herited skin disorder, striate palmoplantar keratoderma. Affected individua ls had a linear pattern of skin thickening on the fingers and palms and cir cumscribed areas of skin thickening on the soles. Affected skin demonstrate d loosening of intercellular connections, disruption of desmosome-keratin i ntermediate filament interactions and a proportion of rudimentary desmosoma l structures. The disorder mapped to chromosome 6p21 with a maximum lod sco re of 10.67. The mutation was a heterozygous C-->T transition in exon 4 of the desmoplakin gene and predicted a premature termination codon in the N-t erminal region of the peptide. This is the first reported mutation of desmo plakin and also the first inherited skin disorder in which haploinsufficien cy of a structural component has been implicated. It identifies dosage of d esmoplakin as critical in maintaining epidermal integrity.