Somitic disruption of GNAS in chick embryos mimics progressive osseous heteroplasia

Abstract

The authors anticipate that this information will provide a more complete view of the patient and disease to the scientific and medical community.

GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders

“…By blocking Gs‐alpha activity, through the use of a dominant negative mutant protein, in a subset of chick somites (the progenitors that give rise to dermis and muscle), they observed rapid ectopic cartilage and bone induction in a distribution corresponding to the injected somites. This suggests that somatic mutations in a progenitor cell of somitic origin, during embryogenesis, may act on a background of germline haploinsufficiency to cause loss of heterozygosity at the GNAS locus and result in a mosaic distribution of subcutaneous ectopic cartilage and bone formation in the progeny of these affected cells [Cairns et al., ]. This is also in agreement with previous studies in conditional knockout mice with biallelic inactivation of Gs alpha, which develop ectopic ossification in the subcutis and skeletal muscles [Castrop et al., ; Regard et al., ].…”

“…A recent study by Cairns et al. () presented an interesting hypothesis to explain the appearance of the POH lesions, which typically follow a dermomyotomal, and sometimes unilateral, distribution. By blocking Gs‐alpha activity, through the use of a dominant negative mutant protein, in a subset of chick somites (the progenitors that give rise to dermis and muscle), they observed rapid ectopic cartilage and bone induction in a distribution corresponding to the injected somites.…”

“…Paternally inherited heterozygous inactivating mutations of Gs‐alpha have also been identified in sporadic and familial cases of progressive osseous heteroplasia (POH) [Shore et al., ]. POH is characterized by dermal ossification during childhood, with progressive and extensive formation of heterotopic bone within deeper tissue, which often occurs along dermatomes [Cairns et al., ]. There is usually no hormone resistance or AHO features, and instead of the subcutaneous calcifications observed in AHO, it is the progression of dermal ossification into deep connective tissues that is the defining feature of POH [Shore et al., ].…”

Natural development of dermal ectopic bone in the american alligator (Alligator mississippiensis) resembles heterotopic ossification disorders in humans

“…Another type of inherited cell‐mediated HO disorder, progressive osseous heteroplasia (POH), is the most severe disorder on a spectrum of HO disorders that share similar genetic aberrations, all of which lead to HO within the dermis and superficial fascia primarily via intramembranous ossification (McCarthy and Sundaram, ; Shore and Kaplan, ; Shore and Kaplan, ; Vashi et al, ; Pignolo et al, ). While much progress is being made toward understanding the molecular mechanisms that contribute to the pathophysiology of POH, the origin of the bone progenitor cells that produce POH lesions remains unidentified (Shore and Kaplan, ; Cairns et al, ; Pignolo et al, ). It has been proposed that adipose tissue might serve as a reservoir of these mesenchymal cells (Pignolo et al, ).…”