Insights into the Role of Cell–Cell Junctions in Physiology and Disease - International Review of Cell and Molecular Biology - page 197

ranging from dermal to cardiovascular to sensory (sight and hearing) condi-
tions ( El-Amraoui and Petit, 2013 ). As an example, P-cadherin is implicated
in a genetic disease with significant dermatologic and retinal relevance
( Sprecher et al., 2001 ). This autosomal-recessive disorder was identified
in hypotrichosis-affected individuals with juvenile macular dystrophy and
leads to early hair loss and progressive macular degeneration. Other loss-
of-function mutations in P-cadherin have recently been reported to be
linked to ectrodactyly-ectodermal dysplasia-clefting syndrome and macular
dystrophy ( Indelman et al., 2002; Kjaer et al., 2005 ).

4.2.2 Desmosomes
While desmosomes are expressed in many cells, there is considerable interest
in their role in epidermal and cardiac disease ( Green and Gaudry, 2000 ).
Mutations in desmosomes were identified in the human plakophilin 1 gene
and subsequently in many other desmosomal components ( McGrath et al.,
1997 ). Collectively, these mutations demonstrate the important role of des-
mosomal proteins in skin, hair, and cardiac function. Many mutations in des-
mosomal components are associated with dominant or recessive disorders
( El-Amraoui and Petit, 2013 ). Additionally, desmosomal cadherins are also
the target of some autoimmune and infectious diseases, such as pemphigus
vulgaris and pemphigus foliaceus ( Amagai et al., 1991; Ding et al., 1997;
Endo et al., 2008; Ishii et al., 1997; Kalantari-Dehaghi et al., 2013 ).
Plakoglobin-deficient transgenic mice exhibit severe cardiac defects and
skin fragility ( Bierkamp et al., 1996 ). In a similar vein, mutations in the
human plakoglobin gene have been found to be the cause of diseases such
as Naxos disease, an autosomal-recessive disorder involving heart, skin, and
hair abnormalities ( McKoy et al., 2000 ). Further, mutations in plakoglobin,
along with many other desmosomal genes, are implicated in arrhythmogenic
right ventricular dysplasia/cardiomyopathy (ARVD/C) ( Asimaki et al.,
2007 ). The characteristic pathological hallmark of ARVD/C is fibrofatty
replacement of healthy cardiac tissue, with myocyte apoptosis and cardiac
rhythm dysfunction ( Corrado et al., 1997 ). Though the exact mechanism
remains elusive, it has been hypothesized that the mutations could affect
the structure and distribution of cell junctional proteins and interfere with
canonical Wnt/ b -catenin signaling pathway ( Fig. 5.2 ). In support of this
hypothesis, nuclear localization of plakoglobin was shown to inhibit
Wnt/ b -catenin signaling, ultimately leading to apoptosis ( Garcia-Gras
et al., 2006; Wei et al., 2011 ). Of considerable interest in researching this
condition is

the clarification of the mechanism underlying disease