HSAN-VI: A spectrum disorder based on dystonin isoform expression

Hereditary sensory and autonomic neuropathy (HSAN-VI) is a recessive genetic disorder that arises because of mutations in the human dystonin gene (DST, previously known as bullous pemphigoid antigen 1). Although initial characterization of HSAN-VI reported it as a sensory neuropathy that was lethal in infancy, we now know of a number of heterozygous mutations in DST that result in milder forms of the disease. Akin to what we observe in the mouse model dystonia musculorum (Dst ), we believe that the heterogeneity of HSAN-VI can be attributed to a number of dystonin isoforms that the mutation affects. Lack of neuronal isoform dystonin-a2 is likely the universal determinant of HSAN-VI because all reported human cases are null for this isoform, as are all Dst mouse alleles. Compensatory mechanisms by intact dystonin-a isoforms also likely play a role in regulating disease severity, although we have yet to determine what specific effect dystonin-a1 and dystonin-a3 have on the pathogenesis of HSAN-VI.