Identification and Functional Characterization of Two Novel NPR2 Mutations in Japanese Patients with Short Stature.

“C-type natriuretic peptide (CNP) – natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. Objective: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. SWe enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. In two subjects, we identified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of CNP-dependent cGMP generation capacities and having dominant negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression.  We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant negative mechanisms vary corresponding to the molecular pathogenesis of the mutations.”

“a gain-of-function NPR2 mutation was identified in patients with tall stature and macrodactyly”

“the effect of a heterozygous NPR2 mutation on height SDS is–1.8 according to the previous report, 2.6 in 100 subjects with short stature, which is defined as height SDS less than –2.0, are expected to be heterozygous for the NPR2 mutation.”