ESPE Abstracts

Introduction: C-type natriuretic peptide (CNP, NPPC gene) and its receptor, natriuretic peptide receptor B (NPR-B, NPR2 gene), is critical for endochondral ossification in growth plate. Biallelic NPR2 mutations are known as acromesomelic dysplasia, type Maroteaux which is characterized by severe short stature. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth.

Objective: The purpose of this study was to identify NPR2 mutation in Korean patients with idiopathic short stature (ISS).

Subjects and Methods: One hundred sixteen subjects (60 males) with non-syndromic ISS from Hallym Medical Center and Korea Medical Center were enrolled. NPPC and NPR2 genes were sequenced and the identified variant was filtered with reference dbSNP and COSMIC database. In silico prediction and in vitro functional analysis using cell-based assay were performed to confirm their protein derangement.

Results: Mean age at ISS diagnosis was 8.0 years and mean (with 95% C.I.) height z-score was -2.65 (-2.72 ~ -2.57). Sixty-two percent (72/116) of subjects had delayed bone ages more than one year compared to their chronological ages. Three pathogenic mutants (R921Q, R495C, Y598N) and one benign variant (R787W) of NPR2 gene was identified and no novel sequence variant in NPPC gene was found in all ISS subjects. Two novel pathogenic mutants (R495C and Y598N) were suggested to be highly pathogenic by Mutation Taster and PolyPhen-2 prediction models. cGMP productions after stimulation with CNP decreased significantly in two novel mutants (R495C and Y598N) expressed constructs-transfected cells compared to those of wild type (WT) NPR-B constructs-transfected cells. When cells cotransfected with mutant and WT NPR-B constructs (1:1), they also showed decreased cGMP production compared to empty vector and WT NPR-B constructs-transfected cells.

Conclusions: Heterozygous NPR2 mutations were found in 2.6% of ISS Korean subjects. This prevalence and a dominant-negative effect of mutant NPR-B on growth signals imply that it is definitely one of genetic causes of ISS.