Spectrum of dominant mutations in the desmosomal cadherin desmoglein 1, causing the skin disease striate palmoplantar keratoderma

Abstract

The adhesive proteins of the desmosome type of cell junction consist of two types of cadherin found exclusively in that structure, the desmogleins and desmocollins, coded by two closely linked loci on human chromosome 18q12.1. Recently we have identified a mutation in the DSG1 gene coding for desmoglein 1 as the cause of the autosomal dominant skin disease striate palmoplantar keratoderma (SPPK) in which affected individuals have marked hyperkeratotic bands on the palms and soles. In the present study we present the complete exon-intron structure of the DSG1 gene, which occupies approximately 43 kb, and intron primers sufficient to amplify all the exons. Using these we have analysed the mutational changes in this gene in five further cases of SPPK. All were heterozygotic mutations in the extracellular domain leading to a truncated protein, due either to an addition or deletion of a single base, or a base change resulting in a stop codon. Three mutations were in exon 9 and one in exon 11, both of which code for part of the third and fourth extracellular domains, and one was in exon 2 coding for part of the prosequence of this processed protein. This latter mutation thus results in the mutant allele synthesising only 25 amino acid residues of the prosequence of the protein so that this is effectively a null mutation implying that dominance in the case of this mutation was caused by haploinsufficiency. The most severe consequences of SPPK mutations are in regions of the body where pressure and abrasion are greatest and where desmosome function is most necessary. SPPK therefore provides a very sensitive measure of desmosomal function.

Desmosomes: a role in cancer?

“…Moreover, enhanced activation of multiple growth and survival pathways, including the phosphatidylinositol 3-kinase, mitogenactivated protein kinase, STAT3 and NF-kB pathways, is observed (Brennan et al, 2007). In humans, patients with Dsg1 haploinsufficiency exhibit thickening of the skin on palms and soles, presumably as a result of defective adhesion and compensatory changes in keratinocyte proliferation and differentiation (Hunt et al, 2001). Overall, these finding indicate that alterations in desmosomal cadherin expression patterns, perhaps through modified intracellular signalling and/or changes in adhesive strength, has fundamental effects on cell behaviour, and can in some situations drive proliferation.…”

The desmosome: cell science lessons from human diseases

“…The autosomaldominant skin disease striate palmoplantar keratoderma is caused by haploinsufficiency of the gene encoding Dsg1 (Hunt et al, 2001;Rickman et al, 1999). Rather than developing blisters in the superficial layers of the epidermis, as occurs in response to pemphigus foliaceus antibodies targeting Dsg1, patients with Dsg1 haploinsufficiency exhibit a thickening of the stratum corneum on the palms and soles (Fig.…”

Desmoglein-1/Erbin interaction suppresses ERK activation to support epidermal differentiation

“…A subset of patients with striate palmoplantar keratoderma (SPPK) are DSG1 deficient, with keratinization defects resembling, to an extent, cutaneous symptoms associated with RASopathies (2,6,7,(15)(16)(17)(18). That these genetic disorders often arise from mutations in ancillary regulators of MAPK signaling highlights the importance of identifying proteins that provide the physical link between DSG1 cytoplasmic domains and the core MAPK machinery.…”