Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI

Paola Fortugno, Francesco Angelucci, Gianluca Cestra, Letizia Camerota, Angelo Salvatore Ferraro, Sonia Cordisco, Luigi Uccioli, Daniele Castiglia, Barbara De Angelis, Ingo Kurth, Uwe Kornak, Francesco Brancati

Research output: Contribution to journalArticle

Abstract

Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Affected individuals harbored the premature termination codon variant p.(Lys4330*) in trans with the p.(Ala203Glu) change affecting a highly conserved residue in an isoform-specific N-terminal region of dystonin. Functional studies showed defects in actin cytoskeleton organization and consequent delayed cell adhesion, spreading and migration, while recombinant p.Ala203Glu dystonin loses the ability to bind actin. Our data aid in the clinical and molecular delineation of HSAN-VI and suggest a central role for cell-motility and cytoskeletal defects in its pathogenesis possibly interfering with the neuronal outgrowth and guidance processes.

Original languageEnglish
Pages (from-to)106-114
Number of pages9
JournalHuman Mutation
Volume40
Issue number1
DOIs
Publication statusE-pub ahead of print - Oct 29 2018

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Keywords

  • BPAG1
  • bullous pemphigoid antigen 1
  • cell adhesion
  • cell migration
  • cytoskeleton
  • dermal fibroblasts
  • DST
  • dystonin
  • hereditary sensory and autonomic neuropathies
  • HSAN

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Fortugno, P., Angelucci, F., Cestra, G., Camerota, L., Ferraro, A. S., Cordisco, S., Uccioli, L., Castiglia, D., De Angelis, B., Kurth, I., Kornak, U., & Brancati, F. (2018). Recessive mutations in the neuronal isoforms of DST, encoding dystonin, lead to abnormal actin cytoskeleton organization and HSAN type VI. Human Mutation, 40(1), 106-114. https://doi.org/10.1002/humu.23678