CNS demyelination in fibrodysplasia ossificans progressiva

Lixin Kan, Joseph A. Kitterman, Daniele Procissi, Salin Chakkalakal, Chian Yu Peng, Tammy L. McGuire, Robert E. Goldsby, Robert J. Pignolo, Eileen M. Shore, Frederick S. Kaplan, John A. Kessler

Research output: Contribution to journalArticlepeer-review

28 Scopus citations


Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder of progressive heterotopic ossification (HO) caused by a recurrent activating mutation of ACVR1/ ALK2, a bone morphogenetic protein (BMP) type I receptor. FOP is characterized by progressive HO, which is associated with inflammation in the setting of dysregulated BMP signaling, however, a variety of atypical neurologic symptoms are also reported by FOP patients. The main objective of this study is to investigate the potential underlying mechanism that is responsible for the observed atypical neurologic symptoms. We evaluated two mouse models of dysregulated BMP signaling for potential CNS pathology through noninvasive magnetic resonance imaging (MRI) studies and histological and immunohistochemical approaches. In one model, BMP4 is over-expressed under the control of the neuron-specific enolase promoter; the second model is a knock-in of a recurrent FOP mutation of ACVR1/ALK2. We also retrospectively examined MRI scans of four FOP patients.We consistently observed demyelinated lesions and focal inflammatory changes of theCNSin both mousemodels but not in wild-type controls, and also found CNS white matter lesions in each of the four FOP patients examined. These findings suggest that dysregulated BMP signaling disturbs normal homeostasis of target tissues, including CNS where focal demyelination may manifest as the neurologic symptoms frequently observed in FOP.

Original languageEnglish (US)
Pages (from-to)2644-2655
Number of pages12
JournalJournal of Neurology
Issue number12
StatePublished - Dec 2012


  • ACVR1/ALK2
  • Animal model
  • Bone morphogenetic protein (BMP)
  • Demyelination
  • Fibrodysplasia ossificans progressiva (FOP)
  • Magnetic resonance imaging (MRI)

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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