Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma.
Desmosomes are highly organized intercellular adhesive junctions that are particularly prominent in epidermis and other tissues experiencing mechanical stress. Desmoplakin, a constitutive component of the desmosomal plaque, is 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 desmoplakin. The identified mutation, resulting in a null allele and haploinsufficiency, was observed in genomic DNA from a kindred with the dominantly inherited skin disorder, striate palmoplantar keratoderma. Affected individuals had a linear pattern of skin thickening on the fingers and palms and circumscribed areas of skin thickening on the soles. Affected skin demonstrated loosening of intercellular connections, disruption of desmosome-keratin intermediate filament interactions and a proportion of rudimentary desmosomal structures. The disorder mapped to chromosome 6p21 with a maximum lod score 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-terminal region of the peptide. This is the first reported mutation of desmo-plakin and also the first inherited skin disorder in which haploinsufficiency of a structural component has been implicated. It identifies dosage of desmoplakin as critical in maintaining epidermal integrity.
Armstrong
D K
DK
Department of Medical Genetics, The Queen's University of Belfast, Belfast City Hospital, Belfast BT9 7AB, UK.
McKenna
K E
KE
Purkis
P E
PE
Green
K J
KJ
Eady
R A
RA
Leigh
I M
IM
Hughes
A E
AE
D001483:Base Sequence; D002874:Chromosome Mapping; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000172:deficiency* / Q000235:genetics*; D004247:DNA / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D051180:Desmoplakins; D003896:Desmosomes / Q000378:metabolism / Q000473:pathology; D005260:Female; D006579:Heterozygote; D006801:Humans; D007645:Keratoderma, Palmoplantar / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D008126:Lod Score; D008297:Male; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation
D003598:Cytoskeletal Proteins; D017931:DNA Primers; C495294:DSP protein, human; D051180:Desmoplakins; D004247:DNA