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J Clin Endocrinol Metab. 2014 Apr;99(4):E713-8. doi: 10.1210/jc.2013-3525. Epub 2014 Jan 28.

Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature.

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  • 1Department of Pediatrics (N.A., S.N., T.H.), Keio University School of Medicine, Tokyo 160-8582, Japan; Department of Pediatrics (T.M.), Asahikawa-Kosei General Hospital, Asahikawa 078-8211, Japan; Department of Basic Sciences (Y.I.), The Japanese Red Cross Hokkaido College of Nursing, Kitami 090-0011, Japan; Tanaka Growth Clinic (T.T.), Tokyo 158-0097, Japan; Department of Medical Subspecialties (S.Y.), National Center for Child Health and Development, Tokyo 157-0074, Japan; Department of Pediatrics (T.O.), Hamamatsu University School of Medicine, Hamamatsu 431-3125, Japan; and Japan Growth Genome Consortium (T.M., Y.I., T.T., S.Y., T.O., T.H.).



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.

[PubMed - indexed for MEDLINE]
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