Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity

Abstract

Epidermal integrity is essential for skin functions. It is maintained by adhesive structures between keratinocytes, mainly the desmosomes and adherens junctions, which provide resistance against mechanical stress and regulate the formation of the skin barrier. As a constituent of both types of intercellular junctions, plakoglobin has multiple interaction partners and mutations in its gene [junction plakoglobin (JUP)] have been associated with mild cutaneous disease, palmoplantar keratoderma and arrhythmogenic heart disease. Here we report a novel lethal phenotype caused by a homozygous nonsense JUP mutation, c.1615C>T, p.Q539X, which is very different from any human or murine JUP phenotype described so far. The patient suffered from severe congenital skin fragility with generalized epidermolysis and massive transcutaneous fluid loss, but apparently no cardiac dysfunction. In contrast to previously reported JUP mutations where truncated proteins were still present, in this case there was complete loss of plakoglobin in the patient's skin, as demonstrated by immunofluorescence and immunoblot analysis. As a consequence, only very few abnormal desmosomes were formed and no adhesion structures between keratinocytes were recognizable. The expression and distribution of desmosomal components was severely affected, suggesting an essential role for plakoglobin in desmosomal assembly. Adherens junction proteins were localized to keratinocyte plasma membrane, but did not provide proper cell-cell adhesion. This lethal congenital epidermolysis bullosa highlights the fundamental role of plakoglobin in epidermal cohesion.

Structural and Functional Diversity of Desmosomes

“…In vitro , keratinocytes isolated from plakoglobin null mice failed to form mechanically contiguous cell sheets (Caldelari et al, 2001;Yin et al, 2005). In agreement with the murine data, analysis of samples isolated from patients with mutant plakoglobin or PKP1 revealed absent or severely compromised epidermal desmosomes, incapable of completing a connection to intermediate fi laments (Pigors et al, 2011;McGrath et al, 1997). Junctions between epithelial cells expressing PKP3 shRNA, likewise, failed to maintain strong intercellular adhesion when challenged mechanically in vitro (Kundu et al, 2008).…”

Desmosomes and Intermediate Filaments: Their Consequences for Tissue Mechanics

“…More recently, a point mutation in the keratin-binding domain of DSP was identified as causing SAM syndrome (McAleer et al 2015). Nonsense, as well as splice site mutations, have been observed in PG causing skin fragility, generalized epidermolysis, palmoplantar keratoderma, and woolly hair (Pigors et al 2011;Li et al 2012). Arrhythmogenic cardiomyopathy (AC) is a rare disease of the heart characterized by progressive myocardial dystrophy with fibro-fatty replacement.…”

Genetic skin diseases related to desmosomes and corneodesmosomes

“…In other cases, complete lack of plakoglobin expression resulted in extreme skin fragility manifested as lethal congenital EB (Table 1, Fig. 2) which lead to death at perinatal stages [19].…”