Unusually severe muscular dystrophy upon in-frame deletion of the dystrophin rod domain and lack of compensation by membrane-localized utrophin

Med. 2023 Apr 14;4(4):245-251.e3. doi: 10.1016/j.medj.2023.02.005. Epub 2023 Mar 10.

Abstract

Background: Utrophin, a dystrophin homolog, is consistently upregulated in muscles of patients with Duchenne muscular dystrophy (DMD) and is believed to partially compensate for the lack of dystrophin in dystrophic muscle. Even though several animal studies support the idea that utrophin can modulate DMD disease severity, human clinical data are scarce.

Methods: We describe a patient with the largest reported in-frame deletion in the DMD gene, including exons 10-60 and thus encompassing the entire rod domain.

Findings: The patient presented with an unusually early and severe progressive weakness, initially suggesting congenital muscular dystrophy. Immunostaining of his muscle biopsy showed that the mutant protein was able to localize at the sarcolemma and stabilize the dystrophin-associated complex. Strikingly, utrophin protein was absent from the sarcolemmal membrane despite the upregulation of utrophin mRNA.

Conclusions: Our results suggest that the internally deleted and dysfunctional dystrophin lacking the entire rod domain may exert a dominant-negative effect by preventing upregulated utrophin protein from reaching the sarcolemmal membrane and thus blocking its partial rescue of muscle function. This unique case may set a lower size limit for similar constructs in potential gene therapy approaches.

Funding: This work was supported by a grant from MDA USA (MDA3896) and by grant number R01AR051999 from NIAMS/NIH to C.G.B.

Keywords: DMD; Duchenne muscular dystrophy; Translation to patients; congenital; deletion; dystrophin; utrophin.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Dystrophin* / genetics
  • Dystrophin* / metabolism
  • Humans
  • Muscles / metabolism
  • Muscles / pathology
  • Muscular Dystrophy, Duchenne* / genetics
  • Muscular Dystrophy, Duchenne* / pathology
  • Sarcolemma / metabolism
  • Sarcolemma / pathology
  • Utrophin / genetics
  • Utrophin / metabolism
  • Utrophin / therapeutic use

Substances

  • Dystrophin
  • Utrophin