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Hereditary sensory and autonomic neuropathy type VI (HSAN-VI) is a recessive human disease that arises from mutations in the dystonin gene ( DST ; also known as Bullous pemphigoid antigen 1 gene). A milder form of HSAN-VI was recently described, resulting from loss of a single dystonin isoform (DST-A2). Similarly, mutations in the mouse dystonin gene ( Dst ) result in severe sensory neuropathy,  dystonia musculorum  ( Dst dt  ). Two  Dst dt   alleles,  Dst dt-Tg4   and  Dst dt-27J  , differ in the severity of disease. The less severe  Dst dt-Tg4   mice have disrupted expression of  Dst-A1  and  -A2  isoforms, while the more severe  Dst dt-27J   allele affects  Dst-A1 ,  -A2  and  -A3  isoforms. As dystonin is a cytoskeletal-linker protein, we evaluated microtubule network integrity within sensory neurons from  Dst dt-Tg4   and  Dst dt-27J   mice. There is a significant reduction in tubulin acetylation in  Dst dt-27J   indicative of microtubule instability and severe microtubule disorganization within sensory axons. However,  Dst dt-Tg4   mice have no change in tubulin acetylation, and microtubule organization was only mildly impaired. Thus, microtubule instability is not central to initiation of  Dst dt   pathogenesis, though it may contribute to disease severity. Maintenance of microtubule stability in  Dst dt-Tg4   dorsal root ganglia could be attributed to an upregulation in  Dst-A3  expression as a compensation for the absence of Dst-A1 and -A2 in  Dst dt-Tg4   sensory neurons. Indeed, knockdown of Dst-A3 in these neurons resulted in a decrease in tubulin acetylation. These findings shed light on the possible compensatory role of dystonin isoforms within HSAN-VI, which might explain the heterogeneity in symptoms within the reported forms of the disease.

human molecular genetics

Dystonin-A3 upregulation is responsible for maintenance of tubulin acetylation in a less severe  dystonia musculorum  mouse model for hereditary sensory and autonomic neuropathy type VI