Selective disruption of muscle and brain-specific BPAG1 isoforms in a girl with a 6;15 translocation, cognitive and motor delay, and tracheo-oesophageal atresia

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Abstract
The protein BPAG1 (MIM: 113810, 600088, http://www.ncbi.nlm.nih.gov/Omim/)/Dystonin is a 230 kDa hemidesmosomal protein belonging to the plakin family, originally identified as one of the major autoantigens of bullous pemphigoid (BP), an autoimmune subepidermal skin blistering disease.1 Mutations in the Dystonin gene result in sensory neuron degeneration in the mutant mouse (dystonia muscolorum (dt/dt)).2–4 The complex organisation of the gene has gradually emerged, initially with the discovery of neuronal isoforms with different NH2-terminal sequences,3,5,6 and more recently with the demonstration of the existence of much longer brain- and muscle-specific isoforms with a complex COOH-terminal organisation.7,8 Although a complete understanding of the variety of BPAG1 isoforms has not been reached yet, a general picture of the organisation of the gene is now available. The epithelial isoform (BPAG1e) is made of a coiled-coil (CC) rod domain flanked by an NH2-terminal head domain called the plakin domain,9 and by a COOH-terminal tail domain made of plectin repeats, capable of binding intermediate filaments (IF) and for this reason called the IF-binding domain (IFBD).9 The plakin domain binds BP180, the other major autoantigen in BP.10 The brain-specific isoform (BPAG1a) has an NH2-terminal actin-binding domain (ABD) made of two calponin homology domains,3,5 a plakin domain, a series of spectrin repeats and a COOH-terminal containing two EF-hand calcium-binding motifs, and a growth arrest-specific 2 (GAS2) microtubule-binding domain.7,11 An alternative NH2-terminal isoform produces a protein with a single calponin-homology domain, destroying the actin-binding activity and at the same time uncovering microtubule-binding activity.6 The muscle-specific isoform (BPAG1b) has a structure very similar to the brain isoform, but includes an additional central IFBD, encoded by a single large exon.7,8 The binding specificity of this domain has not been tested yet. BPAG1 /Dystonin is …