Submission Details

The gene DST was discovered in and named after a mouse line exhibiting a dystonia-like phenotype that was later found to be caused by sensory ataxia (PMIDs, among others: 14188280, 9242412). With a severe sensory and autonomic phenotype, the first human family was described in 2012 (PMID: 22522446). Milder subtypes were reported reminding of hereditary sensory and autonomic neuropathy, but including distal motor involvement as well (PMIDs: 28468842, 30371979), or of a CMT2 (PMID: 32802955) phenotype without autonomic signs. The clinical severeness seems to correlate with the number and pattern of DST isoforms affected by the respective mutations (PMID: 32802955). While neuropathy phenotypes cluster around the a and b, and especially the a2 and b2 isoforms, the e (for epidermal) isoform is strictly associated with epidermolysis bullosa (20164846, 22113475), a likewise recessive disease that come with abnormal skin blistering, but without neuropathy. In one family, the affected individuals manifested with a mixed epidermolysis bullosa and neuropathy phenotype (PMID: 31633269), which correlated with one of the two mutations affecting both the a and b as well as the e isoform. Based on the aforementioned and further mouse models (PMIDs: 7736575, 9242412, 27693510, 24381311), several authors studied the protein expression in multiple parts of the nervous system (PMIDs: 9242412, 22522446), its biochemical function including axonal transport (PMID: 14581450) and ER shaping (PMID: 18638474), and reported on partial rescue by expressing the a2 isoform (PMID: 24381311). With this broad and replicated clinical and experimental evidence, we conclude that the gene disease relationship for DST and autosomal recessive axonal neuropathy is definitive.