title: Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia.
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.
authors.affiliation: Program in Cellular, Molecular and Developmental Biology, Sackler School of Graduate Biomedical Sciences, Tufts University, Boston, Massachusetts 02111, USA.
authors.forename: Dana M
authors.initials: DM
authors.lastname: Cairns
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Pignolo
authors.forename: Tomoya
authors.initials: T
authors.lastname: Uchimura
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Brennan
authors.forename: Carter M
authors.initials: CM
authors.lastname: Lindborg
authors.forename: Meiqi
authors.initials: M
authors.lastname: Xu
authors.forename: Frederick S
authors.initials: FS
authors.lastname: Kaplan
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Shore
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D030161:Avian Proteins / Q000235:genetics* / Q000378:metabolism; D002642:Chick Embryo; D002648:Child; D002675:Child, Preschool; D004195:Disease Models, Animal; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019656:Loss of Heterozygosity; D020125:Mutation, Missense; D009999:Ossification, Heterotopic / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019170:Somites / Q000378:metabolism*; D055815:Young Adult
chemical_list: D030161:Avian Proteins; D019205:GTP-Binding Protein alpha Subunits, Gs