A Homozygous Nonsense Mutation within the Dystonin Gene Coding for the Coiled-Coil Domain of the Epithelial Isoform of BPAG1 Underlies a New Subtype of Autosomal Recessive Epidermolysis Bullosa Simplex

Abstract

Epidermolysis bullosa (EB) is a group of autosomal dominant and recessive blistering skin diseases in which pathogenic mutations have been reported in 13 different genes encoding structural proteins involved in keratinocyte integrity, as well as cell-matrix or cell-cell adhesion. We now report an inherited skin fragility disorder with a homozygous nonsense mutation in the dystonin gene (DST) that encodes the coiled-coil domain of the epithelial isoform of bullous pemphigoid antigen 1, BPAG1-e (also known as BP230). The mutation, p.Gln1124X, leads to the loss of hemidesmosomal inner plaques and a complete absence of skin immunostaining for BPAG1-e, as well as reduced labeling for plectin, the beta4 integrin subunit, and for type XVII collagen. The 38-year-old affected individual has lifelong generalized trauma-induced spontaneous blisters and erosions, particularly around the ankles. In addition, he experiences episodic numbness in his limbs, which started at the age of 37 years. These neurological symptoms may also be due to DST gene mutation, although he has a concomitant diagnosis of CADASIL (cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy), a cerebral small-vessel arteriopathy, which thus complicates the genotype-phenotype interpretation. With regard to skin blistering, the clinicopathological findings expand the molecular basis of EB by identifying BPAG1-e pathology in a new form of autosomal recessive EB simplex.

Axonopathy in the Central Nervous System Is the Hallmark of Mice with a Novel Intragenic Null Mutation of Dystonin

“…Characteristics are a progressive loss of coordination of the limbs (ataxia) and an early death (Kothary et al 1988;Guo et al 1995). There are only few reports about patients with mutations of the human dystonin gene (Giorda et al 2004;Groves et al 2010;Edvardson et al 2012).Several dystonin isoforms are generated from one genomic locus of 400 kb. They are expressed in the central nervous system (CNS) (predominant neuronal isoform "a," 617 kDa and "n," 344 kDa), muscles (predominant muscle isoform "b," 834 kDa), and skin (predominant skin isoform "e," 302 kDa) ( Figure 1 Pool et al 2005).…”

“…They are expressed in the central nervous system (CNS) (predominant neuronal isoform "a," 617 kDa and "n," 344 kDa), muscles (predominant muscle isoform "b," 834 kDa), and skin (predominant skin isoform "e," 302 kDa) ( Figure 1 Pool et al 2005). In human patients, mutation of genes ranges from single base pair (bp) deletion and point mutation to translocation (Giorda et al 2004;Groves et al 2010;Edvardson et al 2012).In this study, a new mutation in the murine dystonin gene, Dst:g.274762_314056del (with respect to genomic DNA), for simplicity called "dt-MP," is described. For this, detailed morphological and molecular analyses of the CNS and peripheral organs were performed.…”

Spectraplakin family proteins – cytoskeletal crosslinkers with versatile roles

“…The phenotype of mice with an epidermal-specific deletion of BPAG1 resembles that of bullous pemphigoid, a human skin disease in which patients produce autoantibodies against BPAG1 (Labib et al, 1986;Mueller et al, 1989;Diaz et al, 1990). Mutations in BPAG1 have also been found in humans with an inherited skin fragility disorder (Groves et al, 2010). Additionally, it has been showed that BPAG1e acts as an essential component of the signaling pathway by which β4-integrin regulates front-to-rear cell polarity and cell migration in skin (Michael et al, 2014).…”

“…As noted above, the epidermis of dt/dt mutant mice resembles that of bullous pemphigoid, a human disorder where autoantibodies against BPAG1 are produced (Diaz et al, 1990;Labib et al, 1986;Mueller et al, 1989). A BPAG1e-specific mutation has been found in humans with an inherited skin fragility disorder (Groves et al, 2010). This mutation within the coiled-coil domain of BPAG1e is associated with the loss of only the hemidesmosomal inner plaque.…”

“…This mutation within the coiled-coil domain of BPAG1e is associated with the loss of only the hemidesmosomal inner plaque. In parallel to skin blistering in BPAG1-null epidermis (Guo et al, 1995), this mutation also resulted in the fragility of the basal cells and an autosomal recessive form of epidermolysis bullosa simplex (EBS) (Groves et al, 2010;Liu et al, 2012). Recent studies in keratinocytes that harbor the naturally occurring mutations have addressed the underlying mechanisms and demonstrated a key role for BPAG1e in regulating keratinocyte adhesion and migration (Hamill et al, 2009;Michael et al, 2014).…”