Effect on Stature of Genetic Variations in the C-Type Natriuretic Peptide Receptor (NPR2)

Robert Olney, Principal Investigator

Funding: Genentech Center for Clinical Research in Endocrinology

Recent data have shown that C-type natriuretic peptide (CNP), acting through its receptor natriuretic peptide receptor-B (NPR-B, gene NPR2) plays an important role in linear growth and may play a role in IGF-I regulation. We have recently shown that, in a large kindred that segregates an inactivating mutation of NPR2, heterozygous carriers are significantly shorter than noncarriers. The prevalence of NPR2 mutations in the general population suggests these might be a significant cause of “idiopathic” short stature. The goal of this project is to test this hypothesis by determining the prevalence of NPR2 abnormalities in people with “idiopathic” short stature. This will be accomplished by sequencing NPR2 in 100 people with “idiopathic” short stature. Genetic abnormalities will be tested for effect on NPR-B function by using site-directed mutagenesis to create NPR2 clones containing the identified variations, transfecting these clones into cells with no endogenous natriuretic peptide receptor expression, and measuring cGMP production in response to CNP. The families of subjects found to carry an NPR2 abnormality will also be studied for phenotype/genotype correlations. Finally, children with idiopathic short stature on growth hormone treatment will be studied to see if being aNPR2 mutation carrier effects response to growth hormone therapy. These studies will provide more information about the role of the CNP/NPR-B system in the regulation of growth and assess whether abnormalities in this system are a cause of short stature. This may result in a change in how we evaluate children with short stature in the future.