Human Molecular Genetics, Vol 8, 971-976, Copyright © 1999 by Oxford University Press
L Rickman, D Simrak, HP Stevens, DM Hunt, IA King, SP Bryant, RA Eady, IM Leigh, J Arnemann, AI Magee, DP Kelsell and RS Buxton
The N-terminal extracellular domain of the cadherins, calcium-dependent
cell adhesion molecules, has been shown by X-ray crystallography to be
involved in two types of interaction: lateral strand dimers and adhesive
dimers. Here we describe the first human mutation in a cadherin present in
desmosome cell junctions that removes a portion of this highly conserved
first extracellular domain. The mutation, in the DSG1 gene coding for a
desmoglein (Dsg1), results in the deletion of the first and much of the
second beta-strand of the first cadherin repeat and part of the first
Ca2+-binding site, and would be expected to compromise strand dimer
formation. It causes a dominantly inherited skin disease, striate
palmoplantar keratoderma (SPPK), mapping to chromosome 18q12.1, in which
affected individuals have marked hyperkeratotic bands on the palms and
soles. In a three generation Dutch family with SPPK, we have found a
G-->A transition in the 3" splice acceptor site of intron 2 of the DSG1
gene which segregated with the disease phenotype. This causes aberrant
splicing of exon 2 to exon 4, which are in-frame, with the consequent
removal of exon 3 encoding part of the prosequence, the mature protein
cleavage site and part of the first extracellular domain. This mutation
emphasizes the importance of this part of the molecule for cadherin
function, and of the Dsg1 protein and hence desmosomes in epidermal
function.
ARTICLES
N-terminal deletion in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma
Division of Membrane Biology, National Institute for Medical Research, The Ridgeway, Mill Hill, London, UK.
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