Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the Dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI

Andrew Ferrier, Tadasu Sato, Yves De Repentigny, Sabrina Gibeault, Kunal Bhanot, Ryan W. O'Meara, Anisha Lynch-Godrei, Samantha F. Kornfeld, Kevin G. Young, Rashmi Kothary

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20 Citations (Scopus)

Abstract

A newly identified lethal form of hereditary sensory and autonomic neuropathy (HSAN), designated HSAN-VI, is caused by a homozygous mutation in the bullous pemphigoid antigen 1 (BPAG1)/dystonin gene (DST). The HSAN-VI mutation impacts all major neuronal BPAG1/dystonin protein isoforms: dystonin-a1, -a2 and -a3. Homozygous mutations in the murine Dst gene cause a severe sensory neuropathy termed dystonia musculorum (dt). Phenotypically, dt mice are similar to HSAN-VI patients, manifesting progressive limb contractures, dystonia, dysautonomia and early postnatal death. To obtain a better molecular understanding of disease pathogenesis in HSAN-VI patients and the dt disorder, we generated transgenic mice expressing a myc-tagged dystonin-a2 protein under the regulation of the neuronal prion protein promoter on the dtTg4/Tg4 background, which is devoid of endogenous dystonin-a1 and -a2, but does express dystonin-a3. Restoring dystonin-a2 expression in the nervous system, particularly within sensory neurons, prevented the disorganization of organelle membranes and microtubule networks, attenuated the degeneration of sensory neuron subtypes and ameliorated the phenotype and increased life span in these mice. Despite these improvements, complete rescue was not observed likely because of inadequate expression of the transgene. Taken together, this study provides needed insight into the molecular basis of the dt disorder and other peripheral neuropathies including HSAN-VI.

Original languageEnglish
Article numberddt663
Pages (from-to)2694-2710
Number of pages17
JournalHuman molecular genetics
Volume23
Issue number10
DOIs
Publication statusPublished - 2014 May

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Ferrier, A., Sato, T., De Repentigny, Y., Gibeault, S., Bhanot, K., O'Meara, R. W., Lynch-Godrei, A., Kornfeld, S. F., Young, K. G., & Kothary, R. (2014). Transgenic expression of neuronal dystonin isoform 2 partially rescues the disease phenotype of the Dystonia musculorum mouse model of hereditary sensory autonomic neuropathy VI. Human molecular genetics, 23(10), 2694-2710. [ddt663]. https://doi.org/10.1093/hmg/ddt663