Constitutive Expression of GsαR201C in Mice Produces a Heritable, Direct Replica of Human Fibrous Dysplasia Bone Pathology and Demonstrates Its Natural History

Abstract

Fibrous dysplasia of bone (FD) is a crippling skeletal disease associated with post zygotic mutations (R201C, R201H) of the gene encoding the α subunit of the stimulatory G protein, Gs. By causing a characteristic structural subversion of bone and bone marrow, the disease results in deformity, hypomineralization, and fracture of the affected bones, with severe morbidity arising in childhood or adolescence. Lack of inheritance of the disease in humans is thought to reflect embryonic lethality of germline-transmitted activating Gsα mutations, which would only survive through somatic mosaicism. We have generated multiple lines of mice that express GsαR201C constitutively and develop an inherited, histopathologically exact replica of human FD. Robust transgene expression in neonatal and embryonic tissues, and embryonic stem (ES) cells was associated with normal development of skeletal tissues and differentiation of skeletal cells. As in humans, FD lesions in mice developed only in the postnatal life; a defined spatial and temporal pattern characterized the onset and progression of lesions across the skeleton. In individual bones, lesions developed through a sequence of three distinct histopathological stages: a primary modeling phase defined by endosteal/medullary excess bone formation, and normal resorption; a secondary phase, with excess, inappropriate remodeling; and a tertiary fibrous dysplastic phase, which reproduced a full-blown replica of the human bone pathology in mice of age ≥1 year. Gsα mutations are sufficient to cause FD, and are per se compatible with germline transmission and normal embryonic development in mice. Our novel murine lines constitute the first model of FD.

RANKL Inhibition in Fibrous Dysplasia of Bone: A Preclinical Study in a Mouse Model of the Human Disease

“…Generation and characterization of EF1α‐G s α R201C mice were reported previously . Briefly, the transgenic line was generated by lentiviral transgenesis using the constitutive promoter human elongation factor 1α (EF1α).…”

Fibrous Dysplasia/McCune-Albright Syndrome: Clinical and Translational Perspectives

“…Saggio et al developed the first inherited, histopathologically similar replica of human FD by generating multiple lines of mice with constitutive G s α R201C expression [55]. Similar to human disease, FD lesions in mice developed only in the postnatal period, however the lesions developed through a sequence of three distinct histopathological stages which do not appear to be characteristic of human disease.…”

Knockin mouse with mutant Gα11 mimics human inherited hypocalcemia and is rescued by pharmacologic inhibitors

“…In humans, highly activating gain-of-function Gα mutations are only encountered as somatic mutations, often in tumors, and are not transmitted through the germline. Interestingly, a transgenic mouse with a heritable Gα s R201C mutation has been described (26). Compared with such oncogenic mutations, which affect residues Arg183 and Gln209 (Gα 11/q nomenclature) that are directly involved in GTP catalysis, the gain-of-function Gα 11 mutations of ADH2 -which affect residues more distant from the GTPase site ( Figure 8D) -appear to have milder effects on G protein function (12); this may explain why these mutations are sufficiently tolerated to allow germline transmission.…”