Matrix metalloproteinase-9 deficiency confers resilience in fibrodysplasia ossificans progressiva in a man and mice.

Single case studies of extraordinary disease resilience may provide therapeutic insight into conditions for which no definitive treatments exist. An otherwise healthy 35-year-old man (patient-R) with the canonical pathogenic ACVR1R206H variant and the classic congenital great toe malformation of fibrodysplasia ossificans progressiva (FOP) had extreme paucity of post-natal heterotopic ossification (HO) and nearly normal mobility. We hypothesized that patient-R lacked a sufficient post-natal inflammatory trigger for HO.

Microcystic lymphatic malformations in Turner syndrome are due to somatic mosaicism of PIK3CA.

Turner syndrome (45,X) is caused by a complete or partial absence of a single X chromosome. Vascular malformations occur due to abnormal development of blood and/or lymphatic vessels. They arise from either somatic or germline pathogenic variants in the genes regulating growth and apoptosis of vascular channels.

Functional Testing of Bone Morphogenetic Protein (BMP) Pathway Variants Identified on Whole-Exome Sequencing in a Patient with Delayed-Onset Fibrodysplasia Ossificans Progressiva (FOP) Using ACVR1 -Specific Human Cellular and Zebrafish Models.

Bone morphogenetic protein (BMP) signaling is critical in skeletal development. Overactivation can trigger heterotopic ossification (HO) as in fibrodysplasia ossificans progressiva (FOP), a rare, progressive disease of massive HO formation. A small subset of FOP patients harboring the causative ACVR1 mutation show strikingly mild or delayed-onset HO, suggesting that genetic variants in the BMP pathway could act as disease modifiers.

Inactivation Alters Subcutaneous Tissues in Progression to Heterotopic Ossification.

Heterotopic ossification (HO), the formation of bone outside of the skeleton, occurs in response to severe trauma and in rare genetic diseases such as progressive osseous heteroplasia (POH). In POH, which is caused by inactivation of , a gene that encodes the alpha stimulatory subunit of G proteins (Gsα), HO typically initiates within subcutaneous soft tissues before progressing to deeper connective tissues. To mimic POH, we used conditional -null mice which form HO in subcutaneous tissues upon inactivation.

Differential Vascularity in Genetic and Nonhereditary Heterotopic Ossification.

Nonhereditary heterotopic ossification (NHO) is a common complication of trauma. Progressive osseous heteroplasia (POH) and fibrodysplasia ossificans progressiva (FOP) are rare genetic causes of heterotopic bone. In this article, we detail the vascular patterning associated with genetic versus NHO.

Ablation of Gsα signaling in osteoclast progenitor cells adversely affects skeletal bone maintenance.

Gsα, the alpha stimulatory subunit of heterotrimeric G proteins that activates downstream signaling through the adenylyl cyclase and cAMP/PKA pathway, plays an important role in bone development and remodeling. The role of Gsα in mesenchymal stem cell (MSC) differentiation to osteoblasts has been demonstrated in several mouse models of Gsα inactivation. Previously, using mice with heterozygous germline deletion of Gsα (Gnas), we identified a novel additional role for Gsα in bone remodeling, and showed the importance of Gnas in maintaining bone quality by regulating osteoclast differentiation and function.