Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia

Dana M. Cairns, Robert Pignolo, Tomoya Uchimura, Tracy A. Brennan, Carter M. Lindborg, Meiqi Xu, Frederick S. Kaplan, Eileen M. Shore, Li Zeng

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Progressive osseous heteroplasia (POH) is a rare developmental disorder of heterotopic ossification (HO) caused by heterozygous inactivating germline mutations in the paternal allele of the GNAS gene. Interestingly, POH lesions have a bewildering mosaic distribution. Using clinical, radiographic, and photographic documentation, we found that most of the 12 individuals studied had a lesional bias toward one side or the other, even showing exclusive sidedness. Most strikingly, all had a dermomyotomal distribution of HO lesions. We hypothesized that somatic mutations in a progenitor cell of somitic origin may act on a background of germline haploinsufficiency to cause loss of heterozygosity at the GNAS locus and lead to the unilateral distribution of POH lesions. Taking advantage of the chick system, we examined our hypothesis by mimicking loss of heterozygosity of GNAS expression using dominant-negative GNAS that was introduced into a subset of chick somites, the progenitors that give rise to dermis and muscle. We observed rapid ectopic cartilage and bone induction at the axial and lateral positions in a unilateral distribution corresponding to the injected somites, which suggests that blocking GNAS activity in a targeted population of progenitor cells can lead to mosaic ectopic ossification reminiscent of that seen in POH.

Original languageEnglish (US)
Pages (from-to)3624-3633
Number of pages10
JournalJournal of Clinical Investigation
Volume123
Issue number8
DOIs
StatePublished - Aug 1 2013
Externally publishedYes

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Chick Embryo
Heterotopic Ossification
Somites
Loss of Heterozygosity
Stem Cells
Haploinsufficiency
Germ-Line Mutation
Dermis
Documentation
Cartilage
Alleles
Bone and Bones
Muscles
Mutation
Progressive Osseous Heteroplasia
Population
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cairns, D. M., Pignolo, R., Uchimura, T., Brennan, T. A., Lindborg, C. M., Xu, M., ... Zeng, L. (2013). Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. Journal of Clinical Investigation, 123(8), 3624-3633. https://doi.org/10.1172/JCI69746

Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. / Cairns, Dana M.; Pignolo, Robert; Uchimura, Tomoya; Brennan, Tracy A.; Lindborg, Carter M.; Xu, Meiqi; Kaplan, Frederick S.; Shore, Eileen M.; Zeng, Li.

In: Journal of Clinical Investigation, Vol. 123, No. 8, 01.08.2013, p. 3624-3633.

Research output: Contribution to journalArticle

Cairns, DM, Pignolo, R, Uchimura, T, Brennan, TA, Lindborg, CM, Xu, M, Kaplan, FS, Shore, EM & Zeng, L 2013, 'Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia', Journal of Clinical Investigation, vol. 123, no. 8, pp. 3624-3633. https://doi.org/10.1172/JCI69746
Cairns, Dana M. ; Pignolo, Robert ; Uchimura, Tomoya ; Brennan, Tracy A. ; Lindborg, Carter M. ; Xu, Meiqi ; Kaplan, Frederick S. ; Shore, Eileen M. ; Zeng, Li. / Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia. In: Journal of Clinical Investigation. 2013 ; Vol. 123, No. 8. pp. 3624-3633.
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