Lynch-Godrei Anisha, Kothary Rashmi
Regenerative Medicine Program (A.L.-G., R.K.), Ottawa Hospital Research Institute; Department of Cellular and Molecular Medicine (A.L.-G., R.K.) and Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa; Department of Medicine (R.K.), University of Ottawa; and Centre for Neuromuscular Disease (R.K.), University of Ottawa, Canada.
Neurol Genet. 2020 Jan 2;6(1):e389. doi: 10.1212/NXG.0000000000000389. eCollection 2020 Feb.
Hereditary sensory and autonomic neuropathy (HSAN-VI) is a recessive genetic disorder that arises because of mutations in the human dystonin gene (, previously known as ). 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 that result in milder forms of the disease. Akin to what we observe in the mouse model ( ), 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 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.
遗传性感觉和自主神经病变（HSAN-VI）是一种隐性遗传疾病，由人类张力蛋白基因（先前称为 ）的突变引起。尽管HSAN-VI的初步特征报告称其为一种在婴儿期致命的感觉神经病变，但我们现在知道该基因中的一些杂合突变会导致病情较轻的形式。类似于我们在小鼠模型 （ ）中观察到的情况，我们认为HSAN-VI的异质性可归因于突变所影响的多种张力蛋白同工型。缺乏神经元同工型张力蛋白-a2可能是HSAN-VI的普遍决定因素，因为所有已报告的人类病例中该同工型均缺失，所有 小鼠等位基因也是如此。完整的张力蛋白-a同工型的补偿机制可能也在调节疾病严重程度中起作用，尽管我们尚未确定张力蛋白-a1和张力蛋白-a3对HSAN-VI发病机制有何种具体影响。
