The BPAG1 locus: alternative splicing produces multiple isoforms with distinct cytoskeletal linker domains, including predominant isoforms in neuronsand muscles

Bullous pemphigoid antigen 1 (BPAG1) is a member of the plakin family with cytoskeletal linker properties. Mutations in BPAG1 cause sensory neuron deg eneration and skin fragility in mice. We have analyzed the BPAG1 locus in d etail and found that it encodes different interaction domains that are comb ined in tissue-specific manners. These domains include an actin-binding dom ain (ABD), a plakin domain, a coiled coil (CC) rod domain, two different po tential intermediate filament-binding domains (IFBDs), a spectrin repeat (S R)-containing rod domain, and a microtubule-binding domain (MTBD). There ar e at least three major forms of BPAG1: BPAG1-e (302 kD), BPAG1-a (615 kD), and BPAG1-b (834 kD). BPAG1-e has been described previously and consists of the plakin domain, the CC rod domain, and the first IFBD. It is the primar y epidermal BPAG1 isoform, and its absence that is the likely cause of skin fragility in mutant mice. BPAG1-a is the major isoform in the nervous syst em and a homologue of the microtubule actin cross-linking factor, MACE. BPA G1-a is composed of the ABD, the plakin domain, the SR-containing rod domai n, and the MTBD. The absence of BPAG1-a is the likely cause of sensory neur odegeneration in mutant mice. BPAG1-b is highly expressed in muscles, and h as extra exons encoding a second IFBD between the plakin and SR-containing rod domains of BPAG1-a.