Key result
NPR2 truncating mutations linked to short stature show severely reduced cGMP production versus wild-type.
Why the study?
Loss-of-function mutations in the NPR2 gene cause short stature, but the identification and functional characterization of NPR2 truncating mutations in Chinese families were lacking.
Observational
p-value: p=<0.05
Supports NPR2 truncating variants in familial short stature via impaired cGMP; leaves open validation in larger cohorts before clinical adoption.
BACKGROUND: The signaling pathway of C-type natriuretic peptide (CNP) and its receptor (natriuretic peptide receptor 2, NPR2) is implicated in the process of endochondral ossification, which is crucial for the linear growth of long bones. Loss-of-function mutations in the NPR2 gene cause short stature. This study aimed to identify and characterize truncating mutations in NPR2 among Chinese families with short stature. METHODS: Whole-exome sequencing and Sanger sequencing were conducted to identify potential mutations. Bioinformatic analysis was utilized to assess the pathogenicity of two mutations. The effects of candidate mutation on gene expression, subcellular localization, protein stability, and protein function were further assessed through in vitro assays. RESULTS: In this study, A novel mutation, c.2629_2630delAG, p.S877Hfs*10 and a previously reported mutation, c.1162 C > T, p.R388* (ClinVar database) in NPR2, were identified in the individuals, and these variants were inherited from the mother and father, respectively. Both mutations were predicted to be deleterious and have a significant impact on protein structure based on bioinformatics analysis. In vitro experiments demonstrated that mutant mRNAs evaded nonsense-mediated mRNA decay (NMD) to produce truncated NPR2 proteins with reduced stability and increased degradation. Furthermore, two truncated NPR2 proteins exhibited impaired localization at the cell membrane and severely reduced ability to stimulate cyclic guanosine monophosphate (cGMP) production in HEK293T cells compared to wild-type (WT) NPR2 (p < 0.05). CONCLUSION: Our study identified two loss-of-function mutations of the NPR2 gene in two Chinese families and offered new insights on the pathogenesis of short stature caused by NPR2 truncating mutations.
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Wei et al. (2025) conducted an observational in Short stature. NPR2 truncating mutations (c.2629_2630delAG and c.1162 C > T) vs. Wild-type (WT) NPR2 was evaluated on Ability to stimulate cyclic guanosine monophosphate (cGMP) production in HEK293T cells (p=<0.05). Two truncating mutations in the NPR2 gene identified in two Chinese families with short stature resulted in severely reduced cGMP production in vitro compared to wild-type NPR2 (p < 0.05).
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