Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1

Abstract

We report a 2-year-old boy with an unusual autosomal recessively inherited skin disease comprising trauma-induced skin fragility and congenital ectodermal dysplasia affecting hair, nails and sweat glands. Skin biopsy showed widening of intercellular spaces between keratinocytes and ultrastructural findings of small, poorly formed desmosomes with reduced connections to the keratin filament cytoskeleton. Immunohistochemical analysis revealed a complete absence of staining for the accessory desmosomal plaque protein plakophilin 1 (PKP1; band 6 protein). The affected individual was a compound heterozygote for null mutations on both alleles of the PKP1 gene. Both mutations occurred within the amino terminus of PKP1, the domain which normally binds the cytoskeletal keratin filament network to the cell membrane. Apart from its localization within desmosomal plaques, PKP1 may also be present within the cytoplasm and nucleus and has putative roles in signal transduction and regulation of gene activity. The clinicopathological observations in this patient demonstrate the relevance of PKP1 to desmosome formation, cutaneous cell-cell adhesion and epidermal development and demonstrate the specific manifestations of human functional knockout mutations in this gene.

Insulin signaling via Akt2 switches plakophilin 1 functions from stabilizing cell adhesion to promoting cell proliferation

“…A strikingly similar phenotype has been reported in patients carrying PKP1 mutations. These patients suffer from defects in hair follicle development (Bergman and Sprecher, 2005), growth retardation and a general failure to thrive (McGrath et al, 1999;Ersoy-Evans et al, 2006;McGrath and Mellerio, 2010), supporting our hypothesis that PKP1 mediates IGF/Akt induced effects in the skin. Moreover, a similar phenotype was reported in PKP3 knockout mice (Sklyarova et al, 2008).…”

The Desmosome

“…For example, patients who suffer from a severe autosomal recessive ectodermal dysplasia and skin fragility syndrome were found to have mutations in PKP1 (McGrath et al 1997;McGrath et al 1999).…”

The desmosome: cell science lessons from human diseases

“…Patients exhibiting a severe autosomal recessive ectodermal dysplasia and skin fragility syndrome were found to have mutations in the armadillo family protein PKP1 (McGrath et al, 1997;McGrath et al, 1999). An affected individual had two copies of PKP1 with premature stop codons, which resulted in a complete absence of the protein.…”

“…There are four plakophilin (PKP) family members: PKP1, PKP2, PKP3 and p0071 (also referred to as PKP4) (Hatzfeld, 2005;Schmidt and Jager, 2005). These molecules are also armadillo family proteins, have diverse binding partners and are thought to facilitate the attachment of intermediate filaments to desmosomal plaques (Kowalczyk et al, 1999;McGrath et al, 1997;McGrath et al, 1999). Deeper in the cytoplasmic plaque of the desmosome is desmoplakin (North et al, 1999), a plakin family member and intermediatefilament-binding protein that appears to be an obligate component of desmosomes across a range of different tissues .…”