Human Molecular Genetics, Vol 8, 143-148, Copyright © 1999 by Oxford University Press
DK Armstrong, KE McKenna, PE Purkis, KJ Green, RA Eady, IM Leigh and AE Hughes
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.
ARTICLES
Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]
Department of Medical Genetics, The Queen's University of Belfast, Belfast City Hospital, Belfast BT9 7AB, UK.
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