Chondrodysplasia with joint dislocations gPAPP type: insight on the molecular basis of the disorder and the role of IMPAD1 in post-natal skeletal development

Chondrodysplasia with joint dislocations gPAPP type is a recessive skeletal disorder characterized by short stature, brachydactyly, congenital joint dislocations, micrognathia, cleft palate and facial dysmorphism. It is caused by mutations in the IMPAD1 gene encoding for gPAPP, a Golgi-resident phosphoadenosine phosphate 3’-phosphatase that hydrolyzes phosphoadenosine phosphate (PAP), the by-product of sulfotransferase reactions, to AMP; thus, this enzyme is involved in sulfation reactions. The function of IMPAD1 has been elucidated by the study of knock-out mice which are lethal at birth preventing to study the role of IMPAD1 in post-natal skeletal development and growth. Patients with chondrodysplasia gPAPP do not have a lethal phenotype; thus, it is crucial to study the role of IMPAD1 in skeletal development after birth using an in vivo model with a less severe phenotype. The objective of this proposal is to study at the morphological, molecular and biochemical level the first Impad1 knock-in mouse, we have recently generated, during post-natal skeletal growth (from birth to 1 month of age) and in adult animals in order to: a) validate the murine strain as an in vivo model of human chondrodysplasia gPAPP; b) contribute to the understanding of the disease-causing mechanism(s) of IMPAD1 mutations. All studies will be performed on the mouse model since they cannot be done in human patients for ethical reasons. These studies are designed to yield a deeper understanding of the function of IMPAD1 and of the pathogenesis of inherited forms of osteoarthropathy, so that effective therapies can be developed