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Naoko Amano, Tokuo Mukai, Yoshiya Ito, Satoshi Narumi, Toshiaki Tanaka, Susumu Yokoya, Tsutomu Ogata, Tomonobu Hasegawa, Identification and Functional Characterization of Two Novel NPR2 Mutations in Japanese Patients With Short Stature, The Journal of Clinical Endocrinology & Metabolism, Volume 99, Issue 4, 1 April 2014, Pages E713–E718, https://doi.org/10.1210/jc.2013-3525
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C-type natriuretic peptide-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.
The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature.
We 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 C-type natriuretic peptide-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.
