4.6 Review

Dynamin 2 (DNM2) as Cause of, and Modifier for, Human Neuromuscular Disease

期刊

NEUROTHERAPEUTICS
卷 15, 期 4, 页码 966-975

出版社

SPRINGER
DOI: 10.1007/s13311-018-00686-0

关键词

Centronuclear myopathy; Charcot-Marie-Tooth neuropathy; DNM2; Congenital neuromuscular disorders; Gene therapy

资金

  1. Natural Sciences and Engineering Research Council (NSERC)
  2. Canadian Institutes of Health Research (CIHR)

向作者/读者索取更多资源

Dynamin 2 (DNM2) belongs to a family of large GTPases that are well known for mediating membrane fission by oligomerizing at the neck of membrane invaginations. Autosomal dominant mutations in the ubiquitously expressed DNM2 cause 2 discrete neuromuscular diseases: autosomal dominant centronuclear myopathy (ADCNM) and dominant intermediate Charcot-Marie-Tooth neuropathy (CMT). CNM and CMT mutations may affect DNM2 in distinct manners: CNM mutations may cause protein hyperactivity with elevated GTPase and fission activities, while CMT mutations could impair DNM2 lipid binding and activity. DNM2 is also a modifier of the X-linked and autosomal recessive forms of CNM, as DNM2 protein levels are upregulated in animal models and patient muscle samples. Strikingly, reducing DNM2 has been shown to revert muscle phenotypes in preclinical models of CNM. As DNM2 emerges as the key player in CNM pathogenesis, the role(s) of DNM2 in skeletal muscle remains unclear. This review aims to provide insights into potential pathomechanisms related to DNM2-CNM mutations, and discuss exciting outcomes of current and future therapeutic approaches targeting DNM2 hyperactivity.

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