The Genetic and Molecular Etiologies of Two Spontaneous Mouse Models of Skeletal Dysplasia and Infertility.

High-throughput genotyping and sequencing technologies have stimulated an accelerated pace of Mendelian gene discovery. Forty-one novel genetic causes of skeletal dysplasia have been uncovered in the last two years. The genetic heterogeneity of the skeletal dysplasias is extremely high, with 450 forms described. Multiple organ systems can be affected, including the reproductive system. I present the discovery of two different genes that are mutated in spontaneously occurring mouse mutants that cause skeletal dysplasia and infertility. These discoveries demonstrate the value of mouse mutations for understanding the pathophysiology of disease and testing treatments. The peewee mouse exhibits female infertility and skeletal dysplasia associated with reduced progression of cells through the zones of the growth plate. The phenotype is caused by a loss-of-function mutation in the gene that encodes natriuretic peptide receptor 2, Npr2. Human NPR2 mutations cause a form of extreme short stature known as acromesomelic dysplasia, Maroteaux type (AMDM). Nothing is known about the fertility of these patients. We demonstrate that Npr2 loss-of-function affects growth by increased activation of the ERK MAPK pathway. We can correct the Npr2pwe/pwe growth defect in explant cultures of embryonic bones with drugs that inhibit MEK1/2 action. We also show that female infertility is rooted in the requirement for Npr2 activation to generate the cGMP necessary to maintain meiotic arrest of oocytes. The chagun mouse exhibits severe short stature and male infertility. The phenotype is caused by a hypomorphic mutation in a gene also mutated in human patients with a form of primordial dwarfism. The fertility of these patients is unknown. I demonstrate that chagun serves as a model for this human disorder. I show that the growth insufficiency is caused by disorganization of the cells at the growth plate, and that male infertility is due to progressive germ cell loss. Both of these mouse mutations model human skeletal dysplasia disorders, predict infertility, illuminate the pathophysiology of the disorders and pave the way for the development of therapeutic interventions to improve growth.PHDCellular & Molecular BiologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/100101/1/kgeister_1.pd