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.

Progressive osseous heteroplasia, as an isolated entity or overlapping with Albright hereditary osteodystrophy

“…In fact, diagnostic mutational spectrum of POH and other forms of GNASbased heterotopic ossification have been suggested (3,21). Given that clinical observation of patients with POH had lesions showing exclusive sided ness, Cairns et al hypothesized that somatic mutations in a progenitor cell of somatic origin may act on a back ground of germline haploinsufficiency to cause loss of heterozygosity at the GNAS locus.…”

“…Progressive osseous heteroplasia (POH; Online Mendelian Inheritance in Man [OMIM] 166350) is a rare condition characterized by invasive heterotopic ossification (1)(2)(3). It typically begins with dermal ossification during infancy and extends to the subcutaneous and deep connective tissues during childhood, leading to severe ankylosis of affected joints and focal growth retardation (1,4,5).…”

“…Furthermore, there are reports of patients with AHO and features of hetero topic ossification (10,11). The GNAS gene, which encodes for the alpha subunit of the stimulatory guanine nucleo tidebinding protein (G s α), has been implicated to account for the overlapping features of POH and PHP Ia (12), as it has been found to be a candidate gene involved in POH (3,6,12,13); AHO (7,14,15); and platelike osteoma cutis (POC) (15). The GNAS gene is located at locus 20q13.3, which is a complex locus subject to imprinting.…”

Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement

“…The ossifications in patients with POH can be limited to or be much more prominent on one side of the body, which suggests that the mechanism of the disease encompasses a second mutational mosaic hit or variations in GNAS imprinting or G s α expression 84 . Brachydactyly.…”

Molecular and Clinical Aspects of Pseudohypoparathyroidism

“…66 Despite the association of germline GNAS mutations with POH, the resulting heterotopic ossification occurs in a mosaic pattern, suggesting that an as yet unknown "second hit" in addition to the GNAS mutation may be necessary. 193 Heterotopic bone likely reflects mis-differentiation of mesenchymal stem cells. 194 Past studies had shown that reducing expression of Gαs in mesenchymal stem cells induces ectopic expression of Cbfa1/Runx2 195 and collagen I and osteopontin, 196 early markers of osteoblast formation.…”